Full text data of THBS1
THBS1
(TSP, TSP1)
[Confidence: high (present in two of the MS resources)]
Thrombospondin-1; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Thrombospondin-1; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00296099
IPI00296099 Thrombospondin 1 precursor, glycoprotein IV, also in mature RBCs Thrombospondin 1 precursor, glycoprotein IV, also in mature RBCs membrane n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a extracelllular region n/a found at its expected molecular weight found at molecular weight
IPI00296099 Thrombospondin 1 precursor, glycoprotein IV, also in mature RBCs Thrombospondin 1 precursor, glycoprotein IV, also in mature RBCs membrane n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a extracelllular region n/a found at its expected molecular weight found at molecular weight
UniProt
P07996
ID TSP1_HUMAN Reviewed; 1170 AA.
AC P07996; A8K6H4; B9EGH6; Q15667;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 31-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 180.
DE RecName: Full=Thrombospondin-1;
DE Flags: Precursor;
GN Name=THBS1; Synonyms=TSP, TSP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Endothelial cell;
RX PubMed=2430973; DOI=10.1083/jcb.103.5.1635;
RA Lawler J., Hynes R.O.;
RT "The structure of human thrombospondin, an adhesive glycoprotein with
RT multiple calcium-binding sites and homologies with several different
RT proteins.";
RL J. Cell Biol. 103:1635-1648(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ALA-523.
RX PubMed=2918029; DOI=10.1083/jcb.108.2.729;
RA Hennessy S.W., Frazier B.A., Kim D.D., Deckwerth T.L.,
RA Baumgartel D.M., Rotwein P., Frazier W.A.;
RT "Complete thrombospondin mRNA sequence includes potential regulatory
RT sites in the 3' untranslated region.";
RL J. Cell Biol. 108:729-736(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-523.
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R.,
RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G.,
RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A.,
RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W.,
RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X.,
RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K.,
RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S.,
RA Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human
RT chromosome 15.";
RL Nature 440:671-675(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-397.
RX PubMed=3030396; DOI=10.1021/bi00374a014;
RA Kobayashi S., Eden-Mccutchan F., Framson P., Bornstein P.;
RT "Partial amino acid sequence of human thrombospondin as determined by
RT analysis of cDNA clones: homology to malarial circumsporozoite
RT proteins.";
RL Biochemistry 25:8418-8425(1986).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-374.
RX PubMed=3461443; DOI=10.1073/pnas.83.15.5449;
RA Dixit V.M., Hennessy S.W., Grant G.A., Rotwein P., Frazier W.A.;
RT "Characterization of a cDNA encoding the heparin and collagen binding
RT domains of human thrombospondin.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:5449-5453(1986).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-166.
RX PubMed=2544587;
RA Laherty C.D., Gierman T.M., Dixit V.M.;
RT "Characterization of the promoter region of the human thrombospondin
RT gene. DNA sequences within the first intron increase transcription.";
RL J. Biol. Chem. 264:11222-11227(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1028-1170.
RA la Fleur M., Jobin C., Gauthier J., Kreis C.G.;
RT "Expression of thrombospondin in chronic inflammation: neutrophils
RT from synovial fluids synthesize a novel 3.9 kb TSP mRNA.";
RL Submitted (DEC-1992) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP INTERACTION WITH CD36.
RX PubMed=1371676; DOI=10.1016/0006-291X(92)91860-S;
RA Asch A.S., Silbiger S., Heimer E., Nachman R.L.;
RT "Thrombospondin sequence motif (CSVTCG) is responsible for CD36
RT binding.";
RL Biochem. Biophys. Res. Commun. 182:1208-1217(1992).
RN [11]
RP GLYCOSYLATION AT TRP-385; SER-394; TRP-438; TRP-441; THR-450; TRP-498
RP AND THR-507.
RC TISSUE=Platelet;
RX PubMed=11067851; DOI=10.1074/jbc.M008073200;
RA Hofsteenge J., Huwiler K.G., Macek B., Hess D., Lawler J.,
RA Mosher D.F., Peter-Katalinic J.;
RT "C-mannosylation and O-fucosylation of the thrombospondin type 1
RT module.";
RL J. Biol. Chem. 276:6485-6498(2001).
RN [12]
RP INTERACTION WITH HRG, AND FUNCTION.
RX PubMed=11134179; DOI=10.1172/JCI9061;
RA Simantov R., Febbraio M., Crombie R., Asch A.S., Nachman R.L.,
RA Silverstein R.L.;
RT "Histidine-rich glycoprotein inhibits the antiangiogenic effect of
RT thrombospondin-1.";
RL J. Clin. Invest. 107:45-52(2001).
RN [13]
RP DISULFIDE BONDS IN THROMBOSPONDIN DOMAIN.
RX PubMed=12450399; DOI=10.1021/bi026463u;
RA Huwiler K.G., Vestling M.M., Annis D.S., Mosher D.F.;
RT "Biophysical characterization, including disulfide bond assignments,
RT of the anti-angiogenic type 1 domains of human thrombospondin-1.";
RL Biochemistry 41:14329-14339(2002).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-248 AND ASN-1067, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1067, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-248, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1067, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 434-546, DISULFIDE BONDS, AND
RP GLYCOSYLATION AT THR-450 AND THR-507.
RX PubMed=12391027; DOI=10.1083/jcb.200206062;
RA Tan K., Duquette M., Liu J.-H., Dong Y., Zhang R., Joachimiak A.,
RA Lawler J., Wang J.-H.;
RT "Crystal structure of the TSP-1 type 1 repeats: a novel layered fold
RT and its biological implication.";
RL J. Cell Biol. 159:373-382(2002).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 834-1170 IN COMPLEX WITH
RP CALCIUM IONS, DISULFIDE BONDS, MUTAGENESIS OF ASN-1067, GLYCOSYLATION
RP AT ASN-1067, CELL ATTACHMENT SITE, AND FUNCTION.
RX PubMed=15014436; DOI=10.1038/sj.emboj.7600166;
RA Kvansakul M., Adams J.C., Hohenester E.;
RT "Structure of a thrombospondin C-terminal fragment reveals a novel
RT calcium core in the type 3 repeats.";
RL EMBO J. 23:1223-1233(2004).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 19-233 IN COMPLEX WITH
RP SYNTHETIC PENTAMERIC HEPARIN, AND DISULFIDE BOND.
RX PubMed=16407063; DOI=10.1016/j.str.2005.09.017;
RA Tan K., Duquette M., Liu J.-H., Zhang R., Joachimiak A., Wang J.-H.,
RA Lawler J.;
RT "The structures of the thrombospondin-1 N-terminal domain and its
RT complex with a synthetic pentameric heparin.";
RL Structure 14:33-42(2006).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 19-257 IN COMPLEXES WITH
RP HEPARIN, MASS SPECTROMETRY, AND GLYCOSYLATION AT ASN-248.
RX PubMed=18065761; DOI=10.1074/jbc.M705203200;
RA Tan K., Duquette M., Liu J.-H., Shanmugasundaram K., Joachimiak A.,
RA Gallagher J.T., Rigby A.C., Wang J.-H., Lawler J.;
RT "Heparin-induced cis- and trans-dimerization modes of the
RT thrombospondin-1 N-terminal domain.";
RL J. Biol. Chem. 283:3932-3941(2008).
CC -!- FUNCTION: Adhesive glycoprotein that mediates cell-to-cell and
CC cell-to-matrix interactions. Binds heparin. May play a role in
CC dentinogenesis and/or maintenance of dentin and dental pulp (By
CC similarity). Ligand for CD36 mediating antiangiogenic properties.
CC Plays a role in ER stress response, via its interaction with the
CC activating transcription factor 6 alpha (ATF6) which produces
CC adaptive ER stress response factors (By similarity).
CC -!- SUBUNIT: Homotrimer; disulfide-linked. Interacts (via the TSP type
CC I repeats) with HRG; the interaction blocks the antiangiogenic
CC effect of THBS1 with CD36 (By similarity). Can bind to fibrinogen,
CC fibronectin, laminin, type V collagen and integrins alpha-V/beta-
CC 1, alpha-V/beta-3 and alpha-IIb/beta-3. Interacts (via the TSP
CC type I repeats) with CD36; the interaction conveys an
CC antiangiogenic effect. Interacts with ATF6 (via lumenal domain)
CC (By similarity).
CC -!- INTERACTION:
CC P01137:TGFB1; NbExp=2; IntAct=EBI-2530274, EBI-779636;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum (By similarity).
CC Sarcoplasmic reticulum (By similarity).
CC -!- SIMILARITY: Belongs to the thrombospondin family.
CC -!- SIMILARITY: Contains 2 EGF-like domains.
CC -!- SIMILARITY: Contains 1 laminin G-like domain.
CC -!- SIMILARITY: Contains 1 TSP C-terminal (TSPC) domain.
CC -!- SIMILARITY: Contains 3 TSP type-1 domains.
CC -!- SIMILARITY: Contains 8 TSP type-3 repeats.
CC -!- SIMILARITY: Contains 1 VWFC domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/THBS1ID42548ch15q15.html";
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DR EMBL; X04665; CAA28370.1; -; mRNA.
DR EMBL; X14787; CAA32889.1; -; mRNA.
DR EMBL; AK291639; BAF84328.1; -; mRNA.
DR EMBL; AC037198; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC136469; AAI36470.1; -; mRNA.
DR EMBL; BC136470; AAI36471.1; -; mRNA.
DR EMBL; M25631; AAA36741.1; -; mRNA.
DR EMBL; M14326; AAA61237.1; ALT_SEQ; mRNA.
DR EMBL; J04835; AAA61178.1; -; Genomic_DNA.
DR EMBL; M99425; AAB59366.1; -; mRNA.
DR PIR; A26155; TSHUP1.
DR RefSeq; NP_003237.2; NM_003246.2.
DR UniGene; Hs.164226; -.
DR PDB; 1LSL; X-ray; 1.90 A; A=434-546.
DR PDB; 1UX6; X-ray; 1.90 A; A=834-1170.
DR PDB; 1Z78; X-ray; 1.80 A; A=19-233.
DR PDB; 1ZA4; X-ray; 1.90 A; A=19-257.
DR PDB; 2ERF; X-ray; 1.45 A; A=25-233.
DR PDB; 2ES3; X-ray; 1.85 A; A/B=25-233.
DR PDB; 2OUH; X-ray; 2.40 A; A/B=19-257.
DR PDB; 2OUJ; X-ray; 1.90 A; A=19-257.
DR PDB; 3R6B; X-ray; 2.40 A; A=434-547.
DR PDBsum; 1LSL; -.
DR PDBsum; 1UX6; -.
DR PDBsum; 1Z78; -.
DR PDBsum; 1ZA4; -.
DR PDBsum; 2ERF; -.
DR PDBsum; 2ES3; -.
DR PDBsum; 2OUH; -.
DR PDBsum; 2OUJ; -.
DR PDBsum; 3R6B; -.
DR ProteinModelPortal; P07996; -.
DR SMR; P07996; 25-233, 434-1170.
DR DIP; DIP-1037N; -.
DR IntAct; P07996; 10.
DR MINT; MINT-6630675; -.
DR STRING; 9606.ENSP00000260356; -.
DR DrugBank; DB00102; Becaplermin.
DR PhosphoSite; P07996; -.
DR UniCarbKB; P07996; -.
DR DMDM; 117949802; -.
DR OGP; P07996; -.
DR PaxDb; P07996; -.
DR PeptideAtlas; P07996; -.
DR PRIDE; P07996; -.
DR Ensembl; ENST00000260356; ENSP00000260356; ENSG00000137801.
DR GeneID; 7057; -.
DR KEGG; hsa:7057; -.
DR UCSC; uc001zkh.3; human.
DR CTD; 7057; -.
DR GeneCards; GC15P039873; -.
DR H-InvDB; HIX0038125; -.
DR HGNC; HGNC:11785; THBS1.
DR HPA; CAB033678; -.
DR MIM; 188060; gene.
DR neXtProt; NX_P07996; -.
DR PharmGKB; PA36497; -.
DR eggNOG; NOG12793; -.
DR HOVERGEN; HBG018006; -.
DR InParanoid; P07996; -.
DR KO; K16857; -.
DR OMA; SPWDICS; -.
DR OrthoDB; EOG76QFGD; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; THBS1; human.
DR EvolutionaryTrace; P07996; -.
DR GeneWiki; Thrombospondin_1; -.
DR GenomeRNAi; 7057; -.
DR NextBio; 27597; -.
DR PMAP-CutDB; P07996; -.
DR PRO; PR:P07996; -.
DR ArrayExpress; P07996; -.
DR Bgee; P07996; -.
DR CleanEx; HS_THBS1; -.
DR Genevestigator; P07996; -.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0031012; C:extracellular matrix; TAS:BHF-UCL.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005577; C:fibrinogen complex; IDA:BHF-UCL.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0016529; C:sarcoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; NAS:BHF-UCL.
DR GO; GO:0070052; F:collagen V binding; IDA:BHF-UCL.
DR GO; GO:0070051; F:fibrinogen binding; IDA:BHF-UCL.
DR GO; GO:0017134; F:fibroblast growth factor binding; IDA:BHF-UCL.
DR GO; GO:0001968; F:fibronectin binding; IDA:BHF-UCL.
DR GO; GO:0008201; F:heparin binding; IDA:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; NAS:BHF-UCL.
DR GO; GO:0005178; F:integrin binding; IMP:BHF-UCL.
DR GO; GO:0043236; F:laminin binding; IDA:BHF-UCL.
DR GO; GO:0030169; F:low-density lipoprotein particle binding; IDA:BHF-UCL.
DR GO; GO:0001786; F:phosphatidylserine binding; IDA:UniProtKB.
DR GO; GO:0043394; F:proteoglycan binding; TAS:BHF-UCL.
DR GO; GO:0050431; F:transforming growth factor beta binding; ISS:BHF-UCL.
DR GO; GO:0000187; P:activation of MAPK activity; IMP:BHF-UCL.
DR GO; GO:0048266; P:behavioral response to pain; ISS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; NAS:BHF-UCL.
DR GO; GO:0007050; P:cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0016477; P:cell migration; IDA:BHF-UCL.
DR GO; GO:0034605; P:cellular response to heat; NAS:BHF-UCL.
DR GO; GO:0002544; P:chronic inflammatory response; IEP:BHF-UCL.
DR GO; GO:0003197; P:endocardial cushion development; IEA:Ensembl.
DR GO; GO:0043652; P:engulfment of apoptotic cell; IDA:BHF-UCL.
DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
DR GO; GO:0003417; P:growth plate cartilage development; IEA:Ensembl.
DR GO; GO:0006955; P:immune response; IEP:BHF-UCL.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0002581; P:negative regulation of antigen processing and presentation of peptide or polysaccharide antigen via MHC class II; IDA:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0010754; P:negative regulation of cGMP-mediated signaling; IDA:BHF-UCL.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0002605; P:negative regulation of dendritic cell antigen processing and presentation; IDA:BHF-UCL.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IDA:BHF-UCL.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; TAS:BHF-UCL.
DR GO; GO:0051918; P:negative regulation of fibrinolysis; IDA:BHF-UCL.
DR GO; GO:0040037; P:negative regulation of fibroblast growth factor receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0051895; P:negative regulation of focal adhesion assembly; TAS:BHF-UCL.
DR GO; GO:0032695; P:negative regulation of interleukin-12 production; IDA:BHF-UCL.
DR GO; GO:0010751; P:negative regulation of nitric oxide mediated signal transduction; IDA:BHF-UCL.
DR GO; GO:0010748; P:negative regulation of plasma membrane long-chain fatty acid transport; IDA:BHF-UCL.
DR GO; GO:0010757; P:negative regulation of plasminogen activation; IDA:BHF-UCL.
DR GO; GO:0003151; P:outflow tract morphogenesis; IEA:Ensembl.
DR GO; GO:0018149; P:peptide cross-linking; IDA:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0010811; P:positive regulation of cell-substrate adhesion; IEA:Ensembl.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; IDA:UniProtKB.
DR GO; GO:1902043; P:positive regulation of extrinsic apoptotic signaling pathway via death domain receptors; IDA:BHF-UCL.
DR GO; GO:0010763; P:positive regulation of fibroblast migration; IDA:BHF-UCL.
DR GO; GO:0043032; P:positive regulation of macrophage activation; IDA:BHF-UCL.
DR GO; GO:0010759; P:positive regulation of macrophage chemotaxis; ISS:BHF-UCL.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IDA:UniProtKB.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IDA:BHF-UCL.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0032914; P:positive regulation of transforming growth factor beta1 production; ISS:BHF-UCL.
DR GO; GO:0045727; P:positive regulation of translation; IDA:BHF-UCL.
DR GO; GO:0042535; P:positive regulation of tumor necrosis factor biosynthetic process; IDA:UniProtKB.
DR GO; GO:0051592; P:response to calcium ion; IDA:BHF-UCL.
DR GO; GO:0042493; P:response to drug; IEP:UniProtKB.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0009749; P:response to glucose stimulus; IDA:BHF-UCL.
DR GO; GO:0001666; P:response to hypoxia; NAS:BHF-UCL.
DR GO; GO:0032026; P:response to magnesium ion; IDA:BHF-UCL.
DR GO; GO:0032570; P:response to progesterone stimulus; TAS:BHF-UCL.
DR GO; GO:0006986; P:response to unfolded protein; IEA:UniProtKB-KW.
DR GO; GO:0002040; P:sprouting angiogenesis; IMP:BHF-UCL.
DR Gene3D; 2.60.120.200; -; 3.
DR InterPro; IPR008985; ConA-like_lec_gl_sf.
DR InterPro; IPR013320; ConA-like_subgrp.
DR InterPro; IPR000742; EG-like_dom.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR013032; EGF-like_CS.
DR InterPro; IPR001791; Laminin_G.
DR InterPro; IPR028499; Thrombospondin-1.
DR InterPro; IPR000884; Thrombospondin_1_rpt.
DR InterPro; IPR003367; Thrombospondin_3-like_rpt.
DR InterPro; IPR017897; Thrombospondin_3_rpt.
DR InterPro; IPR008859; Thrombospondin_C.
DR InterPro; IPR001007; VWF_C.
DR PANTHER; PTHR10199:SF53; PTHR10199:SF53; 1.
DR Pfam; PF07645; EGF_CA; 1.
DR Pfam; PF00090; TSP_1; 3.
DR Pfam; PF02412; TSP_3; 7.
DR Pfam; PF05735; TSP_C; 1.
DR Pfam; PF00093; VWC; 1.
DR SMART; SM00181; EGF; 3.
DR SMART; SM00209; TSP1; 3.
DR SMART; SM00210; TSPN; 1.
DR SMART; SM00214; VWC; 1.
DR SUPFAM; SSF49899; SSF49899; 2.
DR SUPFAM; SSF82895; SSF82895; 3.
DR PROSITE; PS00022; EGF_1; FALSE_NEG.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 2.
DR PROSITE; PS50025; LAM_G_DOMAIN; FALSE_NEG.
DR PROSITE; PS50092; TSP1; 3.
DR PROSITE; PS51234; TSP3; 8.
DR PROSITE; PS51236; TSP_CTER; 1.
DR PROSITE; PS01208; VWFC_1; 1.
DR PROSITE; PS50184; VWFC_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Cell adhesion; Complete proteome;
KW Disulfide bond; EGF-like domain; Endoplasmic reticulum; Glycoprotein;
KW Heparin-binding; Polymorphism; Reference proteome; Repeat;
KW Sarcoplasmic reticulum; Signal; Unfolded protein response.
FT SIGNAL 1 18
FT CHAIN 19 1170 Thrombospondin-1.
FT /FTId=PRO_0000035842.
FT DOMAIN 65 270 Laminin G-like.
FT DOMAIN 316 373 VWFC.
FT DOMAIN 379 429 TSP type-1 1.
FT DOMAIN 435 490 TSP type-1 2.
FT DOMAIN 492 547 TSP type-1 3.
FT DOMAIN 547 587 EGF-like 1.
FT DOMAIN 646 690 EGF-like 2.
FT REPEAT 691 726 TSP type-3 1.
FT REPEAT 727 762 TSP type-3 2.
FT REPEAT 763 785 TSP type-3 3.
FT REPEAT 786 821 TSP type-3 4.
FT REPEAT 822 844 TSP type-3 5.
FT REPEAT 845 882 TSP type-3 6.
FT REPEAT 883 918 TSP type-3 7.
FT REPEAT 919 954 TSP type-3 8.
FT DOMAIN 958 1170 TSP C-terminal.
FT REGION 47 95 Heparin-binding.
FT MOTIF 926 928 Cell attachment site (Probable).
FT CARBOHYD 248 248 N-linked (GlcNAc...) (Probable).
FT CARBOHYD 360 360 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 385 385 C-linked (Man).
FT /FTId=CAR_000205.
FT CARBOHYD 394 394 O-linked (Fuc...).
FT /FTId=CAR_000206.
FT CARBOHYD 438 438 C-linked (Man).
FT /FTId=CAR_000207.
FT CARBOHYD 441 441 C-linked (Man).
FT /FTId=CAR_000208.
FT CARBOHYD 450 450 O-linked (Fuc...).
FT /FTId=CAR_000209.
FT CARBOHYD 498 498 C-linked (Man).
FT /FTId=CAR_000210.
FT CARBOHYD 507 507 O-linked (Fuc...).
FT /FTId=CAR_000211.
FT CARBOHYD 708 708 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1067 1067 N-linked (GlcNAc...).
FT DISULFID 171 232
FT DISULFID 270 270 Interchain (Probable).
FT DISULFID 274 274 Interchain (Probable).
FT DISULFID 391 423
FT DISULFID 395 428
FT DISULFID 406 413
FT DISULFID 447 484
FT DISULFID 451 489
FT DISULFID 462 474
FT DISULFID 504 541
FT DISULFID 508 546
FT DISULFID 519 531
FT DISULFID 551 562 By similarity.
FT DISULFID 556 572 By similarity.
FT DISULFID 575 586 By similarity.
FT DISULFID 592 608 By similarity.
FT DISULFID 599 617 By similarity.
FT DISULFID 620 644 By similarity.
FT DISULFID 650 663 By similarity.
FT DISULFID 657 676 By similarity.
FT DISULFID 678 689 By similarity.
FT DISULFID 705 713 By similarity.
FT DISULFID 718 738 By similarity.
FT DISULFID 754 774 By similarity.
FT DISULFID 777 797 By similarity.
FT DISULFID 813 833 By similarity.
FT DISULFID 836 856
FT DISULFID 874 894
FT DISULFID 910 930
FT DISULFID 946 1167
FT VARIANT 24 24 S -> A (in dbSNP:rs41515347).
FT /FTId=VAR_052657.
FT VARIANT 523 523 T -> A (in dbSNP:rs2292305).
FT /FTId=VAR_028938.
FT VARIANT 700 700 N -> S (in dbSNP:rs2228262).
FT /FTId=VAR_028939.
FT MUTAGEN 1067 1067 N->K: Loss of N-glycosylation site.
FT CONFLICT 84 84 A -> T (in Ref. 1; CAA28370 and 8;
FT AAA61178).
FT CONFLICT 546 546 C -> Y (in Ref. 3; BAF84328).
FT CONFLICT 1008 1008 F -> S (in Ref. 3; BAF84328).
FT STRAND 30 32
FT HELIX 33 37
FT TURN 38 41
FT STRAND 44 49
FT STRAND 58 62
FT HELIX 64 66
FT HELIX 72 85
FT STRAND 87 96
FT STRAND 101 109
FT STRAND 115 122
FT TURN 123 126
FT STRAND 127 134
FT STRAND 137 145
FT STRAND 150 161
FT STRAND 164 169
FT TURN 170 172
FT STRAND 173 178
FT HELIX 183 185
FT HELIX 191 194
FT STRAND 195 200
FT TURN 203 205
FT STRAND 210 218
FT HELIX 223 228
FT TURN 229 231
FT STRAND 450 459
FT STRAND 478 485
FT STRAND 507 509
FT STRAND 511 516
FT STRAND 535 541
FT TURN 838 840
FT STRAND 849 852
FT TURN 854 856
FT STRAND 865 867
FT HELIX 869 871
FT STRAND 888 890
FT HELIX 892 894
FT STRAND 901 903
FT HELIX 905 907
FT TURN 909 912
FT STRAND 924 926
FT HELIX 928 930
FT STRAND 937 939
FT TURN 941 943
FT STRAND 961 965
FT STRAND 986 988
FT STRAND 995 1014
FT STRAND 1022 1031
FT STRAND 1034 1043
FT STRAND 1051 1053
FT STRAND 1059 1067
FT HELIX 1074 1081
FT STRAND 1082 1084
FT TURN 1087 1089
FT STRAND 1090 1095
FT STRAND 1107 1115
FT TURN 1116 1119
FT STRAND 1120 1127
FT STRAND 1130 1134
FT STRAND 1146 1154
FT STRAND 1156 1167
SQ SEQUENCE 1170 AA; 129383 MW; 74749B2418E0943B CRC64;
MGLAWGLGVL FLMHVCGTNR IPESGGDNSV FDIFELTGAA RKGSGRRLVK GPDPSSPAFR
IEDANLIPPV PDDKFQDLVD AVRAEKGFLL LASLRQMKKT RGTLLALERK DHSGQVFSVV
SNGKAGTLDL SLTVQGKQHV VSVEEALLAT GQWKSITLFV QEDRAQLYID CEKMENAELD
VPIQSVFTRD LASIARLRIA KGGVNDNFQG VLQNVRFVFG TTPEDILRNK GCSSSTSVLL
TLDNNVVNGS SPAIRTNYIG HKTKDLQAIC GISCDELSSM VLELRGLRTI VTTLQDSIRK
VTEENKELAN ELRRPPLCYH NGVQYRNNEE WTVDSCTECH CQNSVTICKK VSCPIMPCSN
ATVPDGECCP RCWPSDSADD GWSPWSEWTS CSTSCGNGIQ QRGRSCDSLN NRCEGSSVQT
RTCHIQECDK RFKQDGGWSH WSPWSSCSVT CGDGVITRIR LCNSPSPQMN GKPCEGEARE
TKACKKDACP INGGWGPWSP WDICSVTCGG GVQKRSRLCN NPTPQFGGKD CVGDVTENQI
CNKQDCPIDG CLSNPCFAGV KCTSYPDGSW KCGACPPGYS GNGIQCTDVD ECKEVPDACF
NHNGEHRCEN TDPGYNCLPC PPRFTGSQPF GQGVEHATAN KQVCKPRNPC TDGTHDCNKN
AKCNYLGHYS DPMYRCECKP GYAGNGIICG EDTDLDGWPN ENLVCVANAT YHCKKDNCPN
LPNSGQEDYD KDGIGDACDD DDDNDKIPDD RDNCPFHYNP AQYDYDRDDV GDRCDNCPYN
HNPDQADTDN NGEGDACAAD IDGDGILNER DNCQYVYNVD QRDTDMDGVG DQCDNCPLEH
NPDQLDSDSD RIGDTCDNNQ DIDEDGHQNN LDNCPYVPNA NQADHDKDGK GDACDHDDDN
DGIPDDKDNC RLVPNPDQKD SDGDGRGDAC KDDFDHDSVP DIDDICPENV DISETDFRRF
QMIPLDPKGT SQNDPNWVVR HQGKELVQTV NCDPGLAVGY DEFNAVDFSG TFFINTERDD
DYAGFVFGYQ SSSRFYVVMW KQVTQSYWDT NPTRAQGYSG LSVKVVNSTT GPGEHLRNAL
WHTGNTPGQV RTLWHDPRHI GWKDFTAYRW RLSHRPKTGF IRVVMYEGKK IMADSGPIYD
KTYAGGRLGL FVFSQEMVFF SDLKYECRDP
//
ID TSP1_HUMAN Reviewed; 1170 AA.
AC P07996; A8K6H4; B9EGH6; Q15667;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 31-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 180.
DE RecName: Full=Thrombospondin-1;
DE Flags: Precursor;
GN Name=THBS1; Synonyms=TSP, TSP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Endothelial cell;
RX PubMed=2430973; DOI=10.1083/jcb.103.5.1635;
RA Lawler J., Hynes R.O.;
RT "The structure of human thrombospondin, an adhesive glycoprotein with
RT multiple calcium-binding sites and homologies with several different
RT proteins.";
RL J. Cell Biol. 103:1635-1648(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ALA-523.
RX PubMed=2918029; DOI=10.1083/jcb.108.2.729;
RA Hennessy S.W., Frazier B.A., Kim D.D., Deckwerth T.L.,
RA Baumgartel D.M., Rotwein P., Frazier W.A.;
RT "Complete thrombospondin mRNA sequence includes potential regulatory
RT sites in the 3' untranslated region.";
RL J. Cell Biol. 108:729-736(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-523.
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R.,
RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G.,
RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A.,
RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W.,
RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X.,
RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K.,
RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S.,
RA Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human
RT chromosome 15.";
RL Nature 440:671-675(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-397.
RX PubMed=3030396; DOI=10.1021/bi00374a014;
RA Kobayashi S., Eden-Mccutchan F., Framson P., Bornstein P.;
RT "Partial amino acid sequence of human thrombospondin as determined by
RT analysis of cDNA clones: homology to malarial circumsporozoite
RT proteins.";
RL Biochemistry 25:8418-8425(1986).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-374.
RX PubMed=3461443; DOI=10.1073/pnas.83.15.5449;
RA Dixit V.M., Hennessy S.W., Grant G.A., Rotwein P., Frazier W.A.;
RT "Characterization of a cDNA encoding the heparin and collagen binding
RT domains of human thrombospondin.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:5449-5453(1986).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-166.
RX PubMed=2544587;
RA Laherty C.D., Gierman T.M., Dixit V.M.;
RT "Characterization of the promoter region of the human thrombospondin
RT gene. DNA sequences within the first intron increase transcription.";
RL J. Biol. Chem. 264:11222-11227(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1028-1170.
RA la Fleur M., Jobin C., Gauthier J., Kreis C.G.;
RT "Expression of thrombospondin in chronic inflammation: neutrophils
RT from synovial fluids synthesize a novel 3.9 kb TSP mRNA.";
RL Submitted (DEC-1992) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP INTERACTION WITH CD36.
RX PubMed=1371676; DOI=10.1016/0006-291X(92)91860-S;
RA Asch A.S., Silbiger S., Heimer E., Nachman R.L.;
RT "Thrombospondin sequence motif (CSVTCG) is responsible for CD36
RT binding.";
RL Biochem. Biophys. Res. Commun. 182:1208-1217(1992).
RN [11]
RP GLYCOSYLATION AT TRP-385; SER-394; TRP-438; TRP-441; THR-450; TRP-498
RP AND THR-507.
RC TISSUE=Platelet;
RX PubMed=11067851; DOI=10.1074/jbc.M008073200;
RA Hofsteenge J., Huwiler K.G., Macek B., Hess D., Lawler J.,
RA Mosher D.F., Peter-Katalinic J.;
RT "C-mannosylation and O-fucosylation of the thrombospondin type 1
RT module.";
RL J. Biol. Chem. 276:6485-6498(2001).
RN [12]
RP INTERACTION WITH HRG, AND FUNCTION.
RX PubMed=11134179; DOI=10.1172/JCI9061;
RA Simantov R., Febbraio M., Crombie R., Asch A.S., Nachman R.L.,
RA Silverstein R.L.;
RT "Histidine-rich glycoprotein inhibits the antiangiogenic effect of
RT thrombospondin-1.";
RL J. Clin. Invest. 107:45-52(2001).
RN [13]
RP DISULFIDE BONDS IN THROMBOSPONDIN DOMAIN.
RX PubMed=12450399; DOI=10.1021/bi026463u;
RA Huwiler K.G., Vestling M.M., Annis D.S., Mosher D.F.;
RT "Biophysical characterization, including disulfide bond assignments,
RT of the anti-angiogenic type 1 domains of human thrombospondin-1.";
RL Biochemistry 41:14329-14339(2002).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-248 AND ASN-1067, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1067, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-248, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1067, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 434-546, DISULFIDE BONDS, AND
RP GLYCOSYLATION AT THR-450 AND THR-507.
RX PubMed=12391027; DOI=10.1083/jcb.200206062;
RA Tan K., Duquette M., Liu J.-H., Dong Y., Zhang R., Joachimiak A.,
RA Lawler J., Wang J.-H.;
RT "Crystal structure of the TSP-1 type 1 repeats: a novel layered fold
RT and its biological implication.";
RL J. Cell Biol. 159:373-382(2002).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 834-1170 IN COMPLEX WITH
RP CALCIUM IONS, DISULFIDE BONDS, MUTAGENESIS OF ASN-1067, GLYCOSYLATION
RP AT ASN-1067, CELL ATTACHMENT SITE, AND FUNCTION.
RX PubMed=15014436; DOI=10.1038/sj.emboj.7600166;
RA Kvansakul M., Adams J.C., Hohenester E.;
RT "Structure of a thrombospondin C-terminal fragment reveals a novel
RT calcium core in the type 3 repeats.";
RL EMBO J. 23:1223-1233(2004).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 19-233 IN COMPLEX WITH
RP SYNTHETIC PENTAMERIC HEPARIN, AND DISULFIDE BOND.
RX PubMed=16407063; DOI=10.1016/j.str.2005.09.017;
RA Tan K., Duquette M., Liu J.-H., Zhang R., Joachimiak A., Wang J.-H.,
RA Lawler J.;
RT "The structures of the thrombospondin-1 N-terminal domain and its
RT complex with a synthetic pentameric heparin.";
RL Structure 14:33-42(2006).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 19-257 IN COMPLEXES WITH
RP HEPARIN, MASS SPECTROMETRY, AND GLYCOSYLATION AT ASN-248.
RX PubMed=18065761; DOI=10.1074/jbc.M705203200;
RA Tan K., Duquette M., Liu J.-H., Shanmugasundaram K., Joachimiak A.,
RA Gallagher J.T., Rigby A.C., Wang J.-H., Lawler J.;
RT "Heparin-induced cis- and trans-dimerization modes of the
RT thrombospondin-1 N-terminal domain.";
RL J. Biol. Chem. 283:3932-3941(2008).
CC -!- FUNCTION: Adhesive glycoprotein that mediates cell-to-cell and
CC cell-to-matrix interactions. Binds heparin. May play a role in
CC dentinogenesis and/or maintenance of dentin and dental pulp (By
CC similarity). Ligand for CD36 mediating antiangiogenic properties.
CC Plays a role in ER stress response, via its interaction with the
CC activating transcription factor 6 alpha (ATF6) which produces
CC adaptive ER stress response factors (By similarity).
CC -!- SUBUNIT: Homotrimer; disulfide-linked. Interacts (via the TSP type
CC I repeats) with HRG; the interaction blocks the antiangiogenic
CC effect of THBS1 with CD36 (By similarity). Can bind to fibrinogen,
CC fibronectin, laminin, type V collagen and integrins alpha-V/beta-
CC 1, alpha-V/beta-3 and alpha-IIb/beta-3. Interacts (via the TSP
CC type I repeats) with CD36; the interaction conveys an
CC antiangiogenic effect. Interacts with ATF6 (via lumenal domain)
CC (By similarity).
CC -!- INTERACTION:
CC P01137:TGFB1; NbExp=2; IntAct=EBI-2530274, EBI-779636;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum (By similarity).
CC Sarcoplasmic reticulum (By similarity).
CC -!- SIMILARITY: Belongs to the thrombospondin family.
CC -!- SIMILARITY: Contains 2 EGF-like domains.
CC -!- SIMILARITY: Contains 1 laminin G-like domain.
CC -!- SIMILARITY: Contains 1 TSP C-terminal (TSPC) domain.
CC -!- SIMILARITY: Contains 3 TSP type-1 domains.
CC -!- SIMILARITY: Contains 8 TSP type-3 repeats.
CC -!- SIMILARITY: Contains 1 VWFC domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/THBS1ID42548ch15q15.html";
CC -----------------------------------------------------------------------
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DR EMBL; X04665; CAA28370.1; -; mRNA.
DR EMBL; X14787; CAA32889.1; -; mRNA.
DR EMBL; AK291639; BAF84328.1; -; mRNA.
DR EMBL; AC037198; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC136469; AAI36470.1; -; mRNA.
DR EMBL; BC136470; AAI36471.1; -; mRNA.
DR EMBL; M25631; AAA36741.1; -; mRNA.
DR EMBL; M14326; AAA61237.1; ALT_SEQ; mRNA.
DR EMBL; J04835; AAA61178.1; -; Genomic_DNA.
DR EMBL; M99425; AAB59366.1; -; mRNA.
DR PIR; A26155; TSHUP1.
DR RefSeq; NP_003237.2; NM_003246.2.
DR UniGene; Hs.164226; -.
DR PDB; 1LSL; X-ray; 1.90 A; A=434-546.
DR PDB; 1UX6; X-ray; 1.90 A; A=834-1170.
DR PDB; 1Z78; X-ray; 1.80 A; A=19-233.
DR PDB; 1ZA4; X-ray; 1.90 A; A=19-257.
DR PDB; 2ERF; X-ray; 1.45 A; A=25-233.
DR PDB; 2ES3; X-ray; 1.85 A; A/B=25-233.
DR PDB; 2OUH; X-ray; 2.40 A; A/B=19-257.
DR PDB; 2OUJ; X-ray; 1.90 A; A=19-257.
DR PDB; 3R6B; X-ray; 2.40 A; A=434-547.
DR PDBsum; 1LSL; -.
DR PDBsum; 1UX6; -.
DR PDBsum; 1Z78; -.
DR PDBsum; 1ZA4; -.
DR PDBsum; 2ERF; -.
DR PDBsum; 2ES3; -.
DR PDBsum; 2OUH; -.
DR PDBsum; 2OUJ; -.
DR PDBsum; 3R6B; -.
DR ProteinModelPortal; P07996; -.
DR SMR; P07996; 25-233, 434-1170.
DR DIP; DIP-1037N; -.
DR IntAct; P07996; 10.
DR MINT; MINT-6630675; -.
DR STRING; 9606.ENSP00000260356; -.
DR DrugBank; DB00102; Becaplermin.
DR PhosphoSite; P07996; -.
DR UniCarbKB; P07996; -.
DR DMDM; 117949802; -.
DR OGP; P07996; -.
DR PaxDb; P07996; -.
DR PeptideAtlas; P07996; -.
DR PRIDE; P07996; -.
DR Ensembl; ENST00000260356; ENSP00000260356; ENSG00000137801.
DR GeneID; 7057; -.
DR KEGG; hsa:7057; -.
DR UCSC; uc001zkh.3; human.
DR CTD; 7057; -.
DR GeneCards; GC15P039873; -.
DR H-InvDB; HIX0038125; -.
DR HGNC; HGNC:11785; THBS1.
DR HPA; CAB033678; -.
DR MIM; 188060; gene.
DR neXtProt; NX_P07996; -.
DR PharmGKB; PA36497; -.
DR eggNOG; NOG12793; -.
DR HOVERGEN; HBG018006; -.
DR InParanoid; P07996; -.
DR KO; K16857; -.
DR OMA; SPWDICS; -.
DR OrthoDB; EOG76QFGD; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; THBS1; human.
DR EvolutionaryTrace; P07996; -.
DR GeneWiki; Thrombospondin_1; -.
DR GenomeRNAi; 7057; -.
DR NextBio; 27597; -.
DR PMAP-CutDB; P07996; -.
DR PRO; PR:P07996; -.
DR ArrayExpress; P07996; -.
DR Bgee; P07996; -.
DR CleanEx; HS_THBS1; -.
DR Genevestigator; P07996; -.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0031012; C:extracellular matrix; TAS:BHF-UCL.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005577; C:fibrinogen complex; IDA:BHF-UCL.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0016529; C:sarcoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; NAS:BHF-UCL.
DR GO; GO:0070052; F:collagen V binding; IDA:BHF-UCL.
DR GO; GO:0070051; F:fibrinogen binding; IDA:BHF-UCL.
DR GO; GO:0017134; F:fibroblast growth factor binding; IDA:BHF-UCL.
DR GO; GO:0001968; F:fibronectin binding; IDA:BHF-UCL.
DR GO; GO:0008201; F:heparin binding; IDA:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; NAS:BHF-UCL.
DR GO; GO:0005178; F:integrin binding; IMP:BHF-UCL.
DR GO; GO:0043236; F:laminin binding; IDA:BHF-UCL.
DR GO; GO:0030169; F:low-density lipoprotein particle binding; IDA:BHF-UCL.
DR GO; GO:0001786; F:phosphatidylserine binding; IDA:UniProtKB.
DR GO; GO:0043394; F:proteoglycan binding; TAS:BHF-UCL.
DR GO; GO:0050431; F:transforming growth factor beta binding; ISS:BHF-UCL.
DR GO; GO:0000187; P:activation of MAPK activity; IMP:BHF-UCL.
DR GO; GO:0048266; P:behavioral response to pain; ISS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; NAS:BHF-UCL.
DR GO; GO:0007050; P:cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0016477; P:cell migration; IDA:BHF-UCL.
DR GO; GO:0034605; P:cellular response to heat; NAS:BHF-UCL.
DR GO; GO:0002544; P:chronic inflammatory response; IEP:BHF-UCL.
DR GO; GO:0003197; P:endocardial cushion development; IEA:Ensembl.
DR GO; GO:0043652; P:engulfment of apoptotic cell; IDA:BHF-UCL.
DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
DR GO; GO:0003417; P:growth plate cartilage development; IEA:Ensembl.
DR GO; GO:0006955; P:immune response; IEP:BHF-UCL.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0002581; P:negative regulation of antigen processing and presentation of peptide or polysaccharide antigen via MHC class II; IDA:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0010754; P:negative regulation of cGMP-mediated signaling; IDA:BHF-UCL.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0002605; P:negative regulation of dendritic cell antigen processing and presentation; IDA:BHF-UCL.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IDA:BHF-UCL.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; TAS:BHF-UCL.
DR GO; GO:0051918; P:negative regulation of fibrinolysis; IDA:BHF-UCL.
DR GO; GO:0040037; P:negative regulation of fibroblast growth factor receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0051895; P:negative regulation of focal adhesion assembly; TAS:BHF-UCL.
DR GO; GO:0032695; P:negative regulation of interleukin-12 production; IDA:BHF-UCL.
DR GO; GO:0010751; P:negative regulation of nitric oxide mediated signal transduction; IDA:BHF-UCL.
DR GO; GO:0010748; P:negative regulation of plasma membrane long-chain fatty acid transport; IDA:BHF-UCL.
DR GO; GO:0010757; P:negative regulation of plasminogen activation; IDA:BHF-UCL.
DR GO; GO:0003151; P:outflow tract morphogenesis; IEA:Ensembl.
DR GO; GO:0018149; P:peptide cross-linking; IDA:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0010811; P:positive regulation of cell-substrate adhesion; IEA:Ensembl.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; IDA:UniProtKB.
DR GO; GO:1902043; P:positive regulation of extrinsic apoptotic signaling pathway via death domain receptors; IDA:BHF-UCL.
DR GO; GO:0010763; P:positive regulation of fibroblast migration; IDA:BHF-UCL.
DR GO; GO:0043032; P:positive regulation of macrophage activation; IDA:BHF-UCL.
DR GO; GO:0010759; P:positive regulation of macrophage chemotaxis; ISS:BHF-UCL.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IDA:UniProtKB.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IDA:BHF-UCL.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0032914; P:positive regulation of transforming growth factor beta1 production; ISS:BHF-UCL.
DR GO; GO:0045727; P:positive regulation of translation; IDA:BHF-UCL.
DR GO; GO:0042535; P:positive regulation of tumor necrosis factor biosynthetic process; IDA:UniProtKB.
DR GO; GO:0051592; P:response to calcium ion; IDA:BHF-UCL.
DR GO; GO:0042493; P:response to drug; IEP:UniProtKB.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0009749; P:response to glucose stimulus; IDA:BHF-UCL.
DR GO; GO:0001666; P:response to hypoxia; NAS:BHF-UCL.
DR GO; GO:0032026; P:response to magnesium ion; IDA:BHF-UCL.
DR GO; GO:0032570; P:response to progesterone stimulus; TAS:BHF-UCL.
DR GO; GO:0006986; P:response to unfolded protein; IEA:UniProtKB-KW.
DR GO; GO:0002040; P:sprouting angiogenesis; IMP:BHF-UCL.
DR Gene3D; 2.60.120.200; -; 3.
DR InterPro; IPR008985; ConA-like_lec_gl_sf.
DR InterPro; IPR013320; ConA-like_subgrp.
DR InterPro; IPR000742; EG-like_dom.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR013032; EGF-like_CS.
DR InterPro; IPR001791; Laminin_G.
DR InterPro; IPR028499; Thrombospondin-1.
DR InterPro; IPR000884; Thrombospondin_1_rpt.
DR InterPro; IPR003367; Thrombospondin_3-like_rpt.
DR InterPro; IPR017897; Thrombospondin_3_rpt.
DR InterPro; IPR008859; Thrombospondin_C.
DR InterPro; IPR001007; VWF_C.
DR PANTHER; PTHR10199:SF53; PTHR10199:SF53; 1.
DR Pfam; PF07645; EGF_CA; 1.
DR Pfam; PF00090; TSP_1; 3.
DR Pfam; PF02412; TSP_3; 7.
DR Pfam; PF05735; TSP_C; 1.
DR Pfam; PF00093; VWC; 1.
DR SMART; SM00181; EGF; 3.
DR SMART; SM00209; TSP1; 3.
DR SMART; SM00210; TSPN; 1.
DR SMART; SM00214; VWC; 1.
DR SUPFAM; SSF49899; SSF49899; 2.
DR SUPFAM; SSF82895; SSF82895; 3.
DR PROSITE; PS00022; EGF_1; FALSE_NEG.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 2.
DR PROSITE; PS50025; LAM_G_DOMAIN; FALSE_NEG.
DR PROSITE; PS50092; TSP1; 3.
DR PROSITE; PS51234; TSP3; 8.
DR PROSITE; PS51236; TSP_CTER; 1.
DR PROSITE; PS01208; VWFC_1; 1.
DR PROSITE; PS50184; VWFC_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Cell adhesion; Complete proteome;
KW Disulfide bond; EGF-like domain; Endoplasmic reticulum; Glycoprotein;
KW Heparin-binding; Polymorphism; Reference proteome; Repeat;
KW Sarcoplasmic reticulum; Signal; Unfolded protein response.
FT SIGNAL 1 18
FT CHAIN 19 1170 Thrombospondin-1.
FT /FTId=PRO_0000035842.
FT DOMAIN 65 270 Laminin G-like.
FT DOMAIN 316 373 VWFC.
FT DOMAIN 379 429 TSP type-1 1.
FT DOMAIN 435 490 TSP type-1 2.
FT DOMAIN 492 547 TSP type-1 3.
FT DOMAIN 547 587 EGF-like 1.
FT DOMAIN 646 690 EGF-like 2.
FT REPEAT 691 726 TSP type-3 1.
FT REPEAT 727 762 TSP type-3 2.
FT REPEAT 763 785 TSP type-3 3.
FT REPEAT 786 821 TSP type-3 4.
FT REPEAT 822 844 TSP type-3 5.
FT REPEAT 845 882 TSP type-3 6.
FT REPEAT 883 918 TSP type-3 7.
FT REPEAT 919 954 TSP type-3 8.
FT DOMAIN 958 1170 TSP C-terminal.
FT REGION 47 95 Heparin-binding.
FT MOTIF 926 928 Cell attachment site (Probable).
FT CARBOHYD 248 248 N-linked (GlcNAc...) (Probable).
FT CARBOHYD 360 360 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 385 385 C-linked (Man).
FT /FTId=CAR_000205.
FT CARBOHYD 394 394 O-linked (Fuc...).
FT /FTId=CAR_000206.
FT CARBOHYD 438 438 C-linked (Man).
FT /FTId=CAR_000207.
FT CARBOHYD 441 441 C-linked (Man).
FT /FTId=CAR_000208.
FT CARBOHYD 450 450 O-linked (Fuc...).
FT /FTId=CAR_000209.
FT CARBOHYD 498 498 C-linked (Man).
FT /FTId=CAR_000210.
FT CARBOHYD 507 507 O-linked (Fuc...).
FT /FTId=CAR_000211.
FT CARBOHYD 708 708 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1067 1067 N-linked (GlcNAc...).
FT DISULFID 171 232
FT DISULFID 270 270 Interchain (Probable).
FT DISULFID 274 274 Interchain (Probable).
FT DISULFID 391 423
FT DISULFID 395 428
FT DISULFID 406 413
FT DISULFID 447 484
FT DISULFID 451 489
FT DISULFID 462 474
FT DISULFID 504 541
FT DISULFID 508 546
FT DISULFID 519 531
FT DISULFID 551 562 By similarity.
FT DISULFID 556 572 By similarity.
FT DISULFID 575 586 By similarity.
FT DISULFID 592 608 By similarity.
FT DISULFID 599 617 By similarity.
FT DISULFID 620 644 By similarity.
FT DISULFID 650 663 By similarity.
FT DISULFID 657 676 By similarity.
FT DISULFID 678 689 By similarity.
FT DISULFID 705 713 By similarity.
FT DISULFID 718 738 By similarity.
FT DISULFID 754 774 By similarity.
FT DISULFID 777 797 By similarity.
FT DISULFID 813 833 By similarity.
FT DISULFID 836 856
FT DISULFID 874 894
FT DISULFID 910 930
FT DISULFID 946 1167
FT VARIANT 24 24 S -> A (in dbSNP:rs41515347).
FT /FTId=VAR_052657.
FT VARIANT 523 523 T -> A (in dbSNP:rs2292305).
FT /FTId=VAR_028938.
FT VARIANT 700 700 N -> S (in dbSNP:rs2228262).
FT /FTId=VAR_028939.
FT MUTAGEN 1067 1067 N->K: Loss of N-glycosylation site.
FT CONFLICT 84 84 A -> T (in Ref. 1; CAA28370 and 8;
FT AAA61178).
FT CONFLICT 546 546 C -> Y (in Ref. 3; BAF84328).
FT CONFLICT 1008 1008 F -> S (in Ref. 3; BAF84328).
FT STRAND 30 32
FT HELIX 33 37
FT TURN 38 41
FT STRAND 44 49
FT STRAND 58 62
FT HELIX 64 66
FT HELIX 72 85
FT STRAND 87 96
FT STRAND 101 109
FT STRAND 115 122
FT TURN 123 126
FT STRAND 127 134
FT STRAND 137 145
FT STRAND 150 161
FT STRAND 164 169
FT TURN 170 172
FT STRAND 173 178
FT HELIX 183 185
FT HELIX 191 194
FT STRAND 195 200
FT TURN 203 205
FT STRAND 210 218
FT HELIX 223 228
FT TURN 229 231
FT STRAND 450 459
FT STRAND 478 485
FT STRAND 507 509
FT STRAND 511 516
FT STRAND 535 541
FT TURN 838 840
FT STRAND 849 852
FT TURN 854 856
FT STRAND 865 867
FT HELIX 869 871
FT STRAND 888 890
FT HELIX 892 894
FT STRAND 901 903
FT HELIX 905 907
FT TURN 909 912
FT STRAND 924 926
FT HELIX 928 930
FT STRAND 937 939
FT TURN 941 943
FT STRAND 961 965
FT STRAND 986 988
FT STRAND 995 1014
FT STRAND 1022 1031
FT STRAND 1034 1043
FT STRAND 1051 1053
FT STRAND 1059 1067
FT HELIX 1074 1081
FT STRAND 1082 1084
FT TURN 1087 1089
FT STRAND 1090 1095
FT STRAND 1107 1115
FT TURN 1116 1119
FT STRAND 1120 1127
FT STRAND 1130 1134
FT STRAND 1146 1154
FT STRAND 1156 1167
SQ SEQUENCE 1170 AA; 129383 MW; 74749B2418E0943B CRC64;
MGLAWGLGVL FLMHVCGTNR IPESGGDNSV FDIFELTGAA RKGSGRRLVK GPDPSSPAFR
IEDANLIPPV PDDKFQDLVD AVRAEKGFLL LASLRQMKKT RGTLLALERK DHSGQVFSVV
SNGKAGTLDL SLTVQGKQHV VSVEEALLAT GQWKSITLFV QEDRAQLYID CEKMENAELD
VPIQSVFTRD LASIARLRIA KGGVNDNFQG VLQNVRFVFG TTPEDILRNK GCSSSTSVLL
TLDNNVVNGS SPAIRTNYIG HKTKDLQAIC GISCDELSSM VLELRGLRTI VTTLQDSIRK
VTEENKELAN ELRRPPLCYH NGVQYRNNEE WTVDSCTECH CQNSVTICKK VSCPIMPCSN
ATVPDGECCP RCWPSDSADD GWSPWSEWTS CSTSCGNGIQ QRGRSCDSLN NRCEGSSVQT
RTCHIQECDK RFKQDGGWSH WSPWSSCSVT CGDGVITRIR LCNSPSPQMN GKPCEGEARE
TKACKKDACP INGGWGPWSP WDICSVTCGG GVQKRSRLCN NPTPQFGGKD CVGDVTENQI
CNKQDCPIDG CLSNPCFAGV KCTSYPDGSW KCGACPPGYS GNGIQCTDVD ECKEVPDACF
NHNGEHRCEN TDPGYNCLPC PPRFTGSQPF GQGVEHATAN KQVCKPRNPC TDGTHDCNKN
AKCNYLGHYS DPMYRCECKP GYAGNGIICG EDTDLDGWPN ENLVCVANAT YHCKKDNCPN
LPNSGQEDYD KDGIGDACDD DDDNDKIPDD RDNCPFHYNP AQYDYDRDDV GDRCDNCPYN
HNPDQADTDN NGEGDACAAD IDGDGILNER DNCQYVYNVD QRDTDMDGVG DQCDNCPLEH
NPDQLDSDSD RIGDTCDNNQ DIDEDGHQNN LDNCPYVPNA NQADHDKDGK GDACDHDDDN
DGIPDDKDNC RLVPNPDQKD SDGDGRGDAC KDDFDHDSVP DIDDICPENV DISETDFRRF
QMIPLDPKGT SQNDPNWVVR HQGKELVQTV NCDPGLAVGY DEFNAVDFSG TFFINTERDD
DYAGFVFGYQ SSSRFYVVMW KQVTQSYWDT NPTRAQGYSG LSVKVVNSTT GPGEHLRNAL
WHTGNTPGQV RTLWHDPRHI GWKDFTAYRW RLSHRPKTGF IRVVMYEGKK IMADSGPIYD
KTYAGGRLGL FVFSQEMVFF SDLKYECRDP
//
MIM
188060
*RECORD*
*FIELD* NO
188060
*FIELD* TI
*188060 THROMBOSPONDIN I; THBS1
;;TSP1
*FIELD* TX
DESCRIPTION
Thrombospondin I is a multimodular secreted protein that associates with
read morethe extracellular matrix and possesses a variety of biologic functions,
including a potent antiangiogenic activity. Other thrombospondin genes
include thrombospondins II (THBS2; 188061), III (THBS3; 188062), and IV
(THBS4; 600715).
CLONING
Thrombospondin (THBS) is a homotrimeric glycoprotein with
disulfide-linked subunits of 180 kD. THBS was first described as a
component of the alpha-granule of platelets, released on platelet
activation. It is associated with the platelet membrane in the presence
of divalent cations and has a role in platelet aggregation. THBS is not
limited to platelets, however. It is synthesized and secreted for
incorporation into the extracellular matrix by a variety of cells
including endothelial cells, fibroblasts, smooth muscle cells, and type
II pneumocytes. THBS binds heparin, sulfatides, fibrinogen, fibronectin,
plasminogen, and type V collagen. Dixit et al. (1986) reported
characterization of a cDNA encoding the N-terminal 376 amino acid
residues of human THBS. Asch et al. (1987) identified an 88-kD
glycoprotein which they concluded functions as the cellular THBS
receptor. Frazier (1987) reviewed the molecular structure of
thrombospondin.
Using real-time RT-PCR, Hirose et al. (2008) detected specific and high
expression levels of both THBS1 and THBS2 in human intervertebral disc
tissue.
GENE FUNCTION
De Fraipont et al. (2000) measured the cytosolic concentrations of 3
proteins involved in angiogenesis, namely, platelet-derived endothelial
cell growth factor (PDECGF; 131222), VEGFA (192240), and THBS1 in a
series of 43 human sporadic adrenocortical tumors. The tumors were
classified as adenomas, transitional tumors, or carcinomas.
PDECGF/thymidine phosphorylase levels were not significantly different
among these 3 groups. One hundred percent of the adenomas and 73% of the
transitional tumors showed VEGFA concentrations under the threshold
value of 107 ng/g protein, whereas 75% of the carcinomas had VEGFA
concentrations above this threshold value. Similarly, 89% of the
adenomas showed THBS1 concentrations above the threshold value of 57
microg/g protein, whereas only 25% of the carcinomas and 33% of the
transitional tumor samples did so. IGF2 (147470) overexpression, a
common genetic alteration of adrenocortical carcinomas, was
significantly correlated with higher VEGFA and lower THBS1
concentrations. The authors concluded that a decrease in THBS1
expression is an event that precedes an increase in VEGFA expression
during adrenocortical tumor progression. The population of premalignant
tumors with low THBS1 and normal VEGFA levels could represent a
selective target for antiangiogenic therapies.
Natural inhibitors of angiogenesis are able to block pathologic
neovascularization without harming the preexisting vasculature. Volpert
et al. (2002) demonstrated that 2 such inhibitors, thrombospondin I and
pigment epithelium-derived factor (172860), derive specificity for
remodeling vessels from their dependence on Fas/Fas ligand (134637;
134638)-mediated apoptosis to block angiogenesis. Both inhibitors
upregulated FasL on endothelial cells. Expression of the essential
partner of FasL, Fas receptor, was low on quiescent endothelial cells
and vessels but greatly enhanced by inducers of angiogenesis, thereby
specifically sensitizing the stimulated cells to apoptosis by
inhibitor-generated FasL. The antiangiogenic activity of thrombospondin
I and pigment epithelium-derived factor both in vitro and in vivo was
dependent on this dual induction of Fas and FasL and the resulting
apoptosis. Volpert et al. (2002) concluded that this example of
cooperation between pro- and antiangiogenic factors in the inhibition of
angiogenesis provides one explanation for the ability of inhibitors to
select remodeling capillaries for destruction.
Volpert et al. (2002) found that Id1 (600349) is a potent inhibitor of
Tsp1 transcription in mouse embryonic fibroblasts. In Id1 null mice,
upregulated expression of Tsp1 led to suppression of angiogenesis.
Chemotherapeutic drugs chronically administered to tumor-bearing mice
using a frequent schedule at doses substantially lower than the maximum
tolerated dose (i.e., metronomic dosing) can cause sustained and potent
antiangiogenic effects by targeting endothelial cells of newly growing
tumor blood vessels. Bocci et al. (2003) found that protracted exposure
of endothelial cells in vitro to low concentrations of several different
anticancer agents caused marked induction of Tsp1. Increases in
circulating Tsp1 were also detected in the plasma of human tumor-bearing
severe combined immunodeficient mice treated with metronomic low-dose
cyclophosphamide. The antiangiogenic and antitumor effects of low-dose
continuous cyclophosphamide were lost in Tsp1-null mice, whereas these
effects were retained by using a maximum tolerated dose of the same
drug. Bocci et al. (2003) concluded that TSP1 is a secondary mediator of
the antiangiogenic effects of at least some low-dose metronomic
chemotherapy regimens.
Christopherson et al. (2005) found that immature but not mature
astrocytes expressed TSP1 and TSP2, and these TSPs promoted central
nervous system (CNS) synaptogenesis in vitro and in vivo. TSPs induced
ultrastructurally normal synapses that were presynaptically active but
postsynaptically silent and worked in concert with other, as yet
unidentified, astrocyte-derived signals to produce functional synapses.
These studies identified TSPs as CNS synaptogenic proteins, provided
evidence that astrocytes are important contributors to synaptogenesis
within the developing CNS, and suggested that TSP1 and TSP2 act as a
permissive switch that times CNS synaptogenesis by enabling neuronal
molecules to assemble into synapses within a specific window of CNS
development.
Isenberg et al. (2005) found that endogenous Tsp1 limited the angiogenic
response to nitric oxide (NO) in mouse muscle explant assays. In human
umbilical vein endothelial cells, TSP1 was a potent antagonist of
NO-induced chemotaxis, adhesion, and proliferation. TSP1 antagonized
these cGMP-dependent endothelial responses to NO both upstream and
downstream of cGMP signaling.
Ridnour et al. (2005) found that slow and prolonged release of NO at
various concentrations produced a triphasic response in TSP1 protein
expression in human umbilical vein endothelial cells. Expression of TSP1
decreased at 0.1 micromolar NO, rebounded at 100 micromolar NO, and
decreased again at 1,000 micromolar NO. These same conditions produced a
dose-dependent increase in TP53 (191170) phosphorylation and inverse
biphasic responses of ERK (see ERK1, or MAPK3; 601795) and MAP kinase
phosphatase-1 (DUSP1; 600714). The growth-stimulating activity of
low-dose NO and the suppression of TSP1 expression were both ERK
dependent. Ridnour et al. (2005) concluded that dose-dependent positive
and negative feedback loops exist between NO and TSP1.
Using cDNA microarrays, Thakar et al. (2005) found that Tsp1 was the
transcript showing highest induction at 3 hours following
ischemia/reperfusion (IR) injury in rat and mouse kidneys. Northern blot
analysis demonstrated that Tsp1 expression was undetectable at baseline,
induced at 3 and 12 hours, and returned to baseline at 48 hours of
reperfusion. Immunocytochemical staining showed injured proximal tubules
were the predominant site of expression of Tsp1 in IR injury and that
Tsp1 colocalized with activated caspase-3 (600636). Addition of purified
Tsp1 to normal rat kidney proximal tubule cells or to cells subjected to
ATP depletion in vitro induced injury, and knockout of Tsp1 in mice
afforded significant protection against IR injury-induced renal failure
and tubular damage. Thakar et al. (2005) concluded that TSP1 is a
regulator of ischemic damage in the kidney and plays a role in the
pathophysiology of ischemic renal failure.
Taxanes, such as taxol and docetaxel, are a family of chemotherapeutic
agents that have antineoplastic effects against a wide range of cancers.
Lih et al. (2006) showed that upregulation of TXR1 (PRR13; 610459)
impeded taxane-induced apoptosis in tumor cells by transcriptionally
downregulating production of TSP1. Decreased TXR1 levels or treatment
with TSP1 or a TSP1 mimetic peptide sensitized cells to taxane
cytotoxicity by activating signaling through CD47 (601028), whereas
interference with CD47 function reduced taxane-induced cell death.
Cellular abundance of TXR1 and TSP1 varied inversely, and taxol
cytotoxicity showed a negative correlation with TXR1 expression and a
positive correlation with TSP1 expression in 13 of 19 cancer cell lines
examined. Lih et al. (2006) concluded that TXR1 is a regulator of TSP1
production.
Staniszewska et al. (2007) identified human THBS1 as a ligand for
alpha-9 (ITGA9; 603963)/beta-1 (ITGB1; 135630) integrin, and they
identified an integrin-binding site within the N-terminal domain (NTD)
of THBS1. Binding of the NTD to human dermal microvascular endothelial
cells expressing alpha-9/beta-1 integrin activated signaling proteins
such as ERK1/ERK2 (MAPK1; 176948) and paxillin (PXN; 602505). Blocking
alpha-9/beta-1 integrin by monoclonal antibody or snake venom
disintegrin inhibited cell proliferation and NTD-induced cell migration.
The THBS1 NTD also induced neovascularization in animal model systems,
and this proangiogenic activity was inhibited by alpha-9/beta-1
inhibitors.
GENE STRUCTURE
Wolf et al. (1990) showed that the type I repeating subunits of
thrombospondin are encoded by symmetrical exons and that the
heparin-binding domain is encoded by a single exon. The THBS1 message is
encoded by 21 exons.
MAPPING
By in situ hybridization, Jaffe et al. (1990) mapped the THBS1 gene to
human 15q15 and the cognate gene to mouse chromosome 2 (region F). Wolf
et al. (1990) localized the THBS1 gene to 15q11-qter by Southern
analysis of human-rodent somatic cell hybrids.
ANIMAL MODEL
To explore the function of thrombospondin I in vivo, Lawler et al.
(1998) disrupted the Thbs1 gene by homologous recombination in the mouse
genome. Platelets from these mice were completely deficient in Thbs1
protein; however, thrombin-induced platelet aggregation was not
diminished. The deficient mice displayed a mild and variable lordotic
curvature of the spine that was apparent from birth. They also displayed
an increase in the number of circulating white blood cells, with
monocytes and eosinophils having the largest percent increases. Although
other major organs showed no abnormalities consistent with high levels
of expression of Thbs1 in lung, Lawler et al. (1998) observed
abnormalities in the lungs of the mice lacking Thbs1. Extensive acute
and organizing pneumonia with neutrophils and macrophages developed by 4
weeks of age. The macrophages stained for hemosiderin, indicating that
diffuse alveolar hemorrhage was occurring. Later, the number of
neutrophils decreased and a striking increase in the number of
hemosiderin-containing macrophages was observed associated with
multiple-lineage epithelial hyperplasia and the deposition of collagen
and elastin. The results indicated that THBS1 is involved in normal lung
homeostasis.
To ascertain the participation of the endogenous angiogenic inhibitor
thrombospondin I in tumor progression, Rodriguez-Manzaneque et al.
(2001) generated mammary tumor-prone mice that either lacked, or
specifically overexpressed, Thbs1 in the mammary gland. Tumor burden and
vasculature were significantly increased in Thbs1-deficient animals, and
capillaries within the tumor appeared distended and sinusoidal. In
contrast, Thbs1 overexpressors showed delayed tumor growth or lacked
frank tumor development. Absence of Thbs1 resulted in increased
association of vascular endothelial growth factor (VEGF; 192240) with
its receptor VEGFR2 (191306) and higher levels of active matrix
metalloproteinase-9 (MMP9; 120361), a molecule previously shown to
facilitate both angiogenesis and tumor invasion. In vitro, enzymatic
activation of pro-MMP9 was suppressed by Thbs1. Together these results
argued for a protective role of endogenous inhibitors of angiogenesis in
tumor growth and implicated Thbs1 in the in vivo regulation of
metalloproteinase-9 activation and VEGF signaling.
Tran and Neary (2006) found that extracellular ATP, through the
activation of P2RY4 receptors (300038), stimulated Tsp1 expression and
release in rat cortical astrocytes and that this nucleotide-induced
increase was mediated by protein kinase signaling pathways. They also
found that Tsp1 expression was increased after mechanical strain using
an in vitro model of CNS trauma and that the increase was again
dependent on P2 receptors and protein kinase signaling.
*FIELD* RF
1. Asch, A. S.; Barnwell, J.; Silverstein, R. L.; Nachman, R. L.:
Isolation of the thrombospondin membrane receptor. J. Clin. Invest. 79:
1054-1061, 1987.
2. Bocci, G.; Francia, G.; Man, S.; Lawler, J.; Kerbel, R. S.: Thrombospondin
1, a mediator of the antiangiogenic effects of low-dose metronomic
chemotherapy. Proc. Nat. Acad. Sci. 100: 12917-12922, 2003.
3. Christopherson, K. S.; Ullian, E. M.; Stokes, C. C. A.; Mullowney,
C. E.; Hell, J. W.; Agah, A.; Lawler, J.; Mosher, D. F.; Bornstein,
P.; Barres, B. A.: Thrombospondins are astrocyte-secreted proteins
that promote CNS synaptogenesis. Cell 120: 421-433, 2005.
4. de Fraipont, F.; El Atifi, M.; Gicquel, C.; Bertagna, X.; Chambaz,
E. M.; Feige, J. J.: Expression of the angiogenesis markers vascular
endothelial growth factor-A, thrombospondin-1, and platelet-derived
endothelial cell growth factor in human sporadic adrenocortical tumors:
correlation with genotypic alterations. J. Clin. Endocr. Metab. 85:
4734-4741, 2000.
5. Dixit, V. M.; Hennessy, S. W.; Grant, G. A.; Rotwein, P.; Frazier,
W. A.: Characterization of a cDNA encoding the heparin and collagen
binding domains of human thrombospondin. Proc. Nat. Acad. Sci. 83:
5449-5453, 1986.
6. Frazier, W. A.: Thrombospondin: a modular adhesive glycoprotein
of platelets and nucleated cells. J. Cell Biol. 105: 625-632, 1987.
7. Hirose, Y.; Chiba, K.; Karasugi, T.; Nakajima, M.; Kawaguchi, Y.;
Mikami, Y.; Furuichi, T.; Mio, F.; Miyake, A.; Miyamoto, T.; Ozaki,
K.; Takahashi, A.; Mizuta, H.; Kubo, T.; Kimura, T.; Tanaka, T.; Toyama,
Y.; Ikegawa, S.: A functional polymorphism in THBS2 that affects
alternative splicing and MMP binding is associated with lumbar-disc
herniation. Am. J. Hum. Genet. 82: 1122-1129, 2008.
8. Isenberg, J. S.; Ridnour, L. A.; Perruccio, E. M.; Espey, M. G.;
Wink, D. A.; Roberts, D. D.: Thrombospondin-1 inhibits endothelial
cell responses to nitric oxide in a cGMP-dependent manner. Proc.
Nat. Acad. Sci. 102: 13141-13146, 2005.
9. Jaffe, E.; Bornstein, P.; Disteche, C. M.: Mapping of the thrombospondin
gene to human chromosome 15 and mouse chromosome 2 by in situ hybridization. Genomics 7:
123-126, 1990.
10. Lawler, J.; Sunday, M.; Thibert, V.; Duquette, M.; George, E.
L.; Rayburn, H.; Hynes, R. O.: Thrombospondin-1 is required for normal
murine pulmonary homeostasis and its absence causes pneumonia. J.
Clin. Invest. 101: 982-992, 1998.
11. Lih, C.-J.; Wei, W.; Cohen, S. N.: Txr1: a transcriptional regulator
of thrombospondin-1 that modulates cellular sensitivity to taxanes. Genes
Dev. 20: 2082-2095, 2006.
12. Ridnour, L. A.; Isenberg, J. S.; Espey, M. G.; Thomas, D. D.;
Roberts, D. D.; Wink, D. A.: Nitric oxide regulates angiogenesis
through a functional switch involving thrombospondin-1. Proc. Nat.
Acad. Sci. 102: 13147-13152, 2005.
13. Rodriguez-Manzaneque, J. C.; Lane, T. F.; Ortega, M. A.; Hynes,
R. O.; Lawler, J.; Iruela-Arispe, M. L.: Thrombospondin-1 suppresses
spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9
and mobilization of vascular endothelial growth factor. Proc. Nat.
Acad. Sci. 98: 12485-12490, 2001.
14. Staniszewska, I.; Zaveri, S.; Del Valle, L.; Oliva, I.; Rothman,
V. L.; Croul, S. E.; Roberts, D. D.; Mosher, D. F.; Tuszynski, G.
P.; Marcinkiewicz, C.: Interaction of alpha-9/beta-1 integrin with
thrombospondin-1 promotes angiogenesis. Circ. Res. 100: 1308-1316,
2007.
15. Thakar, C. V.; Zahedi, K.; Revelo, M. P.; Wang, Z.; Burnham, C.
E.; Barone, S.; Bevans, S.; Lentsch, A. B.; Rabb, H.; Soleimani, M.
: Identification of thrombospondin 1 (TSP-1) as a novel mediator of
cell injury in kidney ischemia. J. Clin. Invest. 115: 3451-3459,
2005. Note: Erratum: J. Clin. Invest. 116: 549 only, 2006.
16. Tran, M. D.; Neary, J. T.: Purinergic signaling induces thrombospondin-1
expression in astrocytes. Proc. Nat. Acad. Sci. 103: 9321-9326,
2006.
17. Volpert, O. V.; Pili, R.; Sikder, H. A.; Nelius, T.; Zaichuk,
T.; Morris, C.; Shiflett, C. B.; Devlin, M. K.; Conant, K.; Alani,
R. M.: Id1 regulates angiogenesis through transcriptional repression
of thrombospondin-1. Cancer Cell 2: 473-483, 2002.
18. Volpert, O. V.; Zaichuk, T.; Zhou, W.; Reiher, F.; Ferguson, T.
A.; Stuart, P. M.; Amin, M.; Bouck, N. P.: Inducer-stimulated Fas
targets activated endothelium for destruction by anti-angiogenic thrombospondin-1
and pigment epithelium-derived factor. Nature Med. 8: 349-357, 2002.
19. Wolf, F. W.; Eddy, R. L.; Shows, T. B.; Dixit, V. M.: Structure
and chromosomal localization of the human thrombospondin gene. Genomics 6:
685-691, 1990.
*FIELD* CN
Marla J. F. O'Neill - updated: 6/10/2008
Patricia A. Hartz - updated: 5/1/2008
Patricia A. Hartz - updated: 10/4/2006
Patricia A. Hartz - updated: 7/28/2006
Patricia A. Hartz - updated: 2/2/2006
Patricia A. Hartz - updated: 1/12/2006
Patricia A. Hartz - updated: 10/13/2005
Stylianos E. Antonarakis - updated: 2/23/2005
Patricia A. Hartz - updated: 2/4/2003
Ada Hamosh - updated: 4/9/2002
Victor A. McKusick - updated: 1/11/2002
John A. Phillips, III - updated: 7/6/2001
Alan F. Scott - updated: 9/17/1995
*FIELD* CD
Victor A. McKusick: 10/16/1986
*FIELD* ED
terry: 11/28/2012
carol: 6/11/2008
terry: 6/10/2008
mgross: 5/1/2008
mgross: 7/25/2007
mgross: 10/4/2006
wwang: 8/8/2006
terry: 7/28/2006
mgross: 2/9/2006
terry: 2/2/2006
wwang: 1/12/2006
mgross: 10/13/2005
mgross: 2/23/2005
mgross: 2/4/2003
cwells: 4/17/2002
cwells: 4/15/2002
cwells: 4/12/2002
terry: 4/9/2002
carol: 1/20/2002
mcapotos: 1/11/2002
alopez: 7/6/2001
carol: 4/13/1998
terry: 3/30/1998
alopez: 6/3/1997
mark: 3/24/1997
mark: 9/18/1995
carol: 4/12/1994
carol: 3/19/1993
supermim: 3/16/1992
carol: 10/25/1991
*RECORD*
*FIELD* NO
188060
*FIELD* TI
*188060 THROMBOSPONDIN I; THBS1
;;TSP1
*FIELD* TX
DESCRIPTION
Thrombospondin I is a multimodular secreted protein that associates with
read morethe extracellular matrix and possesses a variety of biologic functions,
including a potent antiangiogenic activity. Other thrombospondin genes
include thrombospondins II (THBS2; 188061), III (THBS3; 188062), and IV
(THBS4; 600715).
CLONING
Thrombospondin (THBS) is a homotrimeric glycoprotein with
disulfide-linked subunits of 180 kD. THBS was first described as a
component of the alpha-granule of platelets, released on platelet
activation. It is associated with the platelet membrane in the presence
of divalent cations and has a role in platelet aggregation. THBS is not
limited to platelets, however. It is synthesized and secreted for
incorporation into the extracellular matrix by a variety of cells
including endothelial cells, fibroblasts, smooth muscle cells, and type
II pneumocytes. THBS binds heparin, sulfatides, fibrinogen, fibronectin,
plasminogen, and type V collagen. Dixit et al. (1986) reported
characterization of a cDNA encoding the N-terminal 376 amino acid
residues of human THBS. Asch et al. (1987) identified an 88-kD
glycoprotein which they concluded functions as the cellular THBS
receptor. Frazier (1987) reviewed the molecular structure of
thrombospondin.
Using real-time RT-PCR, Hirose et al. (2008) detected specific and high
expression levels of both THBS1 and THBS2 in human intervertebral disc
tissue.
GENE FUNCTION
De Fraipont et al. (2000) measured the cytosolic concentrations of 3
proteins involved in angiogenesis, namely, platelet-derived endothelial
cell growth factor (PDECGF; 131222), VEGFA (192240), and THBS1 in a
series of 43 human sporadic adrenocortical tumors. The tumors were
classified as adenomas, transitional tumors, or carcinomas.
PDECGF/thymidine phosphorylase levels were not significantly different
among these 3 groups. One hundred percent of the adenomas and 73% of the
transitional tumors showed VEGFA concentrations under the threshold
value of 107 ng/g protein, whereas 75% of the carcinomas had VEGFA
concentrations above this threshold value. Similarly, 89% of the
adenomas showed THBS1 concentrations above the threshold value of 57
microg/g protein, whereas only 25% of the carcinomas and 33% of the
transitional tumor samples did so. IGF2 (147470) overexpression, a
common genetic alteration of adrenocortical carcinomas, was
significantly correlated with higher VEGFA and lower THBS1
concentrations. The authors concluded that a decrease in THBS1
expression is an event that precedes an increase in VEGFA expression
during adrenocortical tumor progression. The population of premalignant
tumors with low THBS1 and normal VEGFA levels could represent a
selective target for antiangiogenic therapies.
Natural inhibitors of angiogenesis are able to block pathologic
neovascularization without harming the preexisting vasculature. Volpert
et al. (2002) demonstrated that 2 such inhibitors, thrombospondin I and
pigment epithelium-derived factor (172860), derive specificity for
remodeling vessels from their dependence on Fas/Fas ligand (134637;
134638)-mediated apoptosis to block angiogenesis. Both inhibitors
upregulated FasL on endothelial cells. Expression of the essential
partner of FasL, Fas receptor, was low on quiescent endothelial cells
and vessels but greatly enhanced by inducers of angiogenesis, thereby
specifically sensitizing the stimulated cells to apoptosis by
inhibitor-generated FasL. The antiangiogenic activity of thrombospondin
I and pigment epithelium-derived factor both in vitro and in vivo was
dependent on this dual induction of Fas and FasL and the resulting
apoptosis. Volpert et al. (2002) concluded that this example of
cooperation between pro- and antiangiogenic factors in the inhibition of
angiogenesis provides one explanation for the ability of inhibitors to
select remodeling capillaries for destruction.
Volpert et al. (2002) found that Id1 (600349) is a potent inhibitor of
Tsp1 transcription in mouse embryonic fibroblasts. In Id1 null mice,
upregulated expression of Tsp1 led to suppression of angiogenesis.
Chemotherapeutic drugs chronically administered to tumor-bearing mice
using a frequent schedule at doses substantially lower than the maximum
tolerated dose (i.e., metronomic dosing) can cause sustained and potent
antiangiogenic effects by targeting endothelial cells of newly growing
tumor blood vessels. Bocci et al. (2003) found that protracted exposure
of endothelial cells in vitro to low concentrations of several different
anticancer agents caused marked induction of Tsp1. Increases in
circulating Tsp1 were also detected in the plasma of human tumor-bearing
severe combined immunodeficient mice treated with metronomic low-dose
cyclophosphamide. The antiangiogenic and antitumor effects of low-dose
continuous cyclophosphamide were lost in Tsp1-null mice, whereas these
effects were retained by using a maximum tolerated dose of the same
drug. Bocci et al. (2003) concluded that TSP1 is a secondary mediator of
the antiangiogenic effects of at least some low-dose metronomic
chemotherapy regimens.
Christopherson et al. (2005) found that immature but not mature
astrocytes expressed TSP1 and TSP2, and these TSPs promoted central
nervous system (CNS) synaptogenesis in vitro and in vivo. TSPs induced
ultrastructurally normal synapses that were presynaptically active but
postsynaptically silent and worked in concert with other, as yet
unidentified, astrocyte-derived signals to produce functional synapses.
These studies identified TSPs as CNS synaptogenic proteins, provided
evidence that astrocytes are important contributors to synaptogenesis
within the developing CNS, and suggested that TSP1 and TSP2 act as a
permissive switch that times CNS synaptogenesis by enabling neuronal
molecules to assemble into synapses within a specific window of CNS
development.
Isenberg et al. (2005) found that endogenous Tsp1 limited the angiogenic
response to nitric oxide (NO) in mouse muscle explant assays. In human
umbilical vein endothelial cells, TSP1 was a potent antagonist of
NO-induced chemotaxis, adhesion, and proliferation. TSP1 antagonized
these cGMP-dependent endothelial responses to NO both upstream and
downstream of cGMP signaling.
Ridnour et al. (2005) found that slow and prolonged release of NO at
various concentrations produced a triphasic response in TSP1 protein
expression in human umbilical vein endothelial cells. Expression of TSP1
decreased at 0.1 micromolar NO, rebounded at 100 micromolar NO, and
decreased again at 1,000 micromolar NO. These same conditions produced a
dose-dependent increase in TP53 (191170) phosphorylation and inverse
biphasic responses of ERK (see ERK1, or MAPK3; 601795) and MAP kinase
phosphatase-1 (DUSP1; 600714). The growth-stimulating activity of
low-dose NO and the suppression of TSP1 expression were both ERK
dependent. Ridnour et al. (2005) concluded that dose-dependent positive
and negative feedback loops exist between NO and TSP1.
Using cDNA microarrays, Thakar et al. (2005) found that Tsp1 was the
transcript showing highest induction at 3 hours following
ischemia/reperfusion (IR) injury in rat and mouse kidneys. Northern blot
analysis demonstrated that Tsp1 expression was undetectable at baseline,
induced at 3 and 12 hours, and returned to baseline at 48 hours of
reperfusion. Immunocytochemical staining showed injured proximal tubules
were the predominant site of expression of Tsp1 in IR injury and that
Tsp1 colocalized with activated caspase-3 (600636). Addition of purified
Tsp1 to normal rat kidney proximal tubule cells or to cells subjected to
ATP depletion in vitro induced injury, and knockout of Tsp1 in mice
afforded significant protection against IR injury-induced renal failure
and tubular damage. Thakar et al. (2005) concluded that TSP1 is a
regulator of ischemic damage in the kidney and plays a role in the
pathophysiology of ischemic renal failure.
Taxanes, such as taxol and docetaxel, are a family of chemotherapeutic
agents that have antineoplastic effects against a wide range of cancers.
Lih et al. (2006) showed that upregulation of TXR1 (PRR13; 610459)
impeded taxane-induced apoptosis in tumor cells by transcriptionally
downregulating production of TSP1. Decreased TXR1 levels or treatment
with TSP1 or a TSP1 mimetic peptide sensitized cells to taxane
cytotoxicity by activating signaling through CD47 (601028), whereas
interference with CD47 function reduced taxane-induced cell death.
Cellular abundance of TXR1 and TSP1 varied inversely, and taxol
cytotoxicity showed a negative correlation with TXR1 expression and a
positive correlation with TSP1 expression in 13 of 19 cancer cell lines
examined. Lih et al. (2006) concluded that TXR1 is a regulator of TSP1
production.
Staniszewska et al. (2007) identified human THBS1 as a ligand for
alpha-9 (ITGA9; 603963)/beta-1 (ITGB1; 135630) integrin, and they
identified an integrin-binding site within the N-terminal domain (NTD)
of THBS1. Binding of the NTD to human dermal microvascular endothelial
cells expressing alpha-9/beta-1 integrin activated signaling proteins
such as ERK1/ERK2 (MAPK1; 176948) and paxillin (PXN; 602505). Blocking
alpha-9/beta-1 integrin by monoclonal antibody or snake venom
disintegrin inhibited cell proliferation and NTD-induced cell migration.
The THBS1 NTD also induced neovascularization in animal model systems,
and this proangiogenic activity was inhibited by alpha-9/beta-1
inhibitors.
GENE STRUCTURE
Wolf et al. (1990) showed that the type I repeating subunits of
thrombospondin are encoded by symmetrical exons and that the
heparin-binding domain is encoded by a single exon. The THBS1 message is
encoded by 21 exons.
MAPPING
By in situ hybridization, Jaffe et al. (1990) mapped the THBS1 gene to
human 15q15 and the cognate gene to mouse chromosome 2 (region F). Wolf
et al. (1990) localized the THBS1 gene to 15q11-qter by Southern
analysis of human-rodent somatic cell hybrids.
ANIMAL MODEL
To explore the function of thrombospondin I in vivo, Lawler et al.
(1998) disrupted the Thbs1 gene by homologous recombination in the mouse
genome. Platelets from these mice were completely deficient in Thbs1
protein; however, thrombin-induced platelet aggregation was not
diminished. The deficient mice displayed a mild and variable lordotic
curvature of the spine that was apparent from birth. They also displayed
an increase in the number of circulating white blood cells, with
monocytes and eosinophils having the largest percent increases. Although
other major organs showed no abnormalities consistent with high levels
of expression of Thbs1 in lung, Lawler et al. (1998) observed
abnormalities in the lungs of the mice lacking Thbs1. Extensive acute
and organizing pneumonia with neutrophils and macrophages developed by 4
weeks of age. The macrophages stained for hemosiderin, indicating that
diffuse alveolar hemorrhage was occurring. Later, the number of
neutrophils decreased and a striking increase in the number of
hemosiderin-containing macrophages was observed associated with
multiple-lineage epithelial hyperplasia and the deposition of collagen
and elastin. The results indicated that THBS1 is involved in normal lung
homeostasis.
To ascertain the participation of the endogenous angiogenic inhibitor
thrombospondin I in tumor progression, Rodriguez-Manzaneque et al.
(2001) generated mammary tumor-prone mice that either lacked, or
specifically overexpressed, Thbs1 in the mammary gland. Tumor burden and
vasculature were significantly increased in Thbs1-deficient animals, and
capillaries within the tumor appeared distended and sinusoidal. In
contrast, Thbs1 overexpressors showed delayed tumor growth or lacked
frank tumor development. Absence of Thbs1 resulted in increased
association of vascular endothelial growth factor (VEGF; 192240) with
its receptor VEGFR2 (191306) and higher levels of active matrix
metalloproteinase-9 (MMP9; 120361), a molecule previously shown to
facilitate both angiogenesis and tumor invasion. In vitro, enzymatic
activation of pro-MMP9 was suppressed by Thbs1. Together these results
argued for a protective role of endogenous inhibitors of angiogenesis in
tumor growth and implicated Thbs1 in the in vivo regulation of
metalloproteinase-9 activation and VEGF signaling.
Tran and Neary (2006) found that extracellular ATP, through the
activation of P2RY4 receptors (300038), stimulated Tsp1 expression and
release in rat cortical astrocytes and that this nucleotide-induced
increase was mediated by protein kinase signaling pathways. They also
found that Tsp1 expression was increased after mechanical strain using
an in vitro model of CNS trauma and that the increase was again
dependent on P2 receptors and protein kinase signaling.
*FIELD* RF
1. Asch, A. S.; Barnwell, J.; Silverstein, R. L.; Nachman, R. L.:
Isolation of the thrombospondin membrane receptor. J. Clin. Invest. 79:
1054-1061, 1987.
2. Bocci, G.; Francia, G.; Man, S.; Lawler, J.; Kerbel, R. S.: Thrombospondin
1, a mediator of the antiangiogenic effects of low-dose metronomic
chemotherapy. Proc. Nat. Acad. Sci. 100: 12917-12922, 2003.
3. Christopherson, K. S.; Ullian, E. M.; Stokes, C. C. A.; Mullowney,
C. E.; Hell, J. W.; Agah, A.; Lawler, J.; Mosher, D. F.; Bornstein,
P.; Barres, B. A.: Thrombospondins are astrocyte-secreted proteins
that promote CNS synaptogenesis. Cell 120: 421-433, 2005.
4. de Fraipont, F.; El Atifi, M.; Gicquel, C.; Bertagna, X.; Chambaz,
E. M.; Feige, J. J.: Expression of the angiogenesis markers vascular
endothelial growth factor-A, thrombospondin-1, and platelet-derived
endothelial cell growth factor in human sporadic adrenocortical tumors:
correlation with genotypic alterations. J. Clin. Endocr. Metab. 85:
4734-4741, 2000.
5. Dixit, V. M.; Hennessy, S. W.; Grant, G. A.; Rotwein, P.; Frazier,
W. A.: Characterization of a cDNA encoding the heparin and collagen
binding domains of human thrombospondin. Proc. Nat. Acad. Sci. 83:
5449-5453, 1986.
6. Frazier, W. A.: Thrombospondin: a modular adhesive glycoprotein
of platelets and nucleated cells. J. Cell Biol. 105: 625-632, 1987.
7. Hirose, Y.; Chiba, K.; Karasugi, T.; Nakajima, M.; Kawaguchi, Y.;
Mikami, Y.; Furuichi, T.; Mio, F.; Miyake, A.; Miyamoto, T.; Ozaki,
K.; Takahashi, A.; Mizuta, H.; Kubo, T.; Kimura, T.; Tanaka, T.; Toyama,
Y.; Ikegawa, S.: A functional polymorphism in THBS2 that affects
alternative splicing and MMP binding is associated with lumbar-disc
herniation. Am. J. Hum. Genet. 82: 1122-1129, 2008.
8. Isenberg, J. S.; Ridnour, L. A.; Perruccio, E. M.; Espey, M. G.;
Wink, D. A.; Roberts, D. D.: Thrombospondin-1 inhibits endothelial
cell responses to nitric oxide in a cGMP-dependent manner. Proc.
Nat. Acad. Sci. 102: 13141-13146, 2005.
9. Jaffe, E.; Bornstein, P.; Disteche, C. M.: Mapping of the thrombospondin
gene to human chromosome 15 and mouse chromosome 2 by in situ hybridization. Genomics 7:
123-126, 1990.
10. Lawler, J.; Sunday, M.; Thibert, V.; Duquette, M.; George, E.
L.; Rayburn, H.; Hynes, R. O.: Thrombospondin-1 is required for normal
murine pulmonary homeostasis and its absence causes pneumonia. J.
Clin. Invest. 101: 982-992, 1998.
11. Lih, C.-J.; Wei, W.; Cohen, S. N.: Txr1: a transcriptional regulator
of thrombospondin-1 that modulates cellular sensitivity to taxanes. Genes
Dev. 20: 2082-2095, 2006.
12. Ridnour, L. A.; Isenberg, J. S.; Espey, M. G.; Thomas, D. D.;
Roberts, D. D.; Wink, D. A.: Nitric oxide regulates angiogenesis
through a functional switch involving thrombospondin-1. Proc. Nat.
Acad. Sci. 102: 13147-13152, 2005.
13. Rodriguez-Manzaneque, J. C.; Lane, T. F.; Ortega, M. A.; Hynes,
R. O.; Lawler, J.; Iruela-Arispe, M. L.: Thrombospondin-1 suppresses
spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9
and mobilization of vascular endothelial growth factor. Proc. Nat.
Acad. Sci. 98: 12485-12490, 2001.
14. Staniszewska, I.; Zaveri, S.; Del Valle, L.; Oliva, I.; Rothman,
V. L.; Croul, S. E.; Roberts, D. D.; Mosher, D. F.; Tuszynski, G.
P.; Marcinkiewicz, C.: Interaction of alpha-9/beta-1 integrin with
thrombospondin-1 promotes angiogenesis. Circ. Res. 100: 1308-1316,
2007.
15. Thakar, C. V.; Zahedi, K.; Revelo, M. P.; Wang, Z.; Burnham, C.
E.; Barone, S.; Bevans, S.; Lentsch, A. B.; Rabb, H.; Soleimani, M.
: Identification of thrombospondin 1 (TSP-1) as a novel mediator of
cell injury in kidney ischemia. J. Clin. Invest. 115: 3451-3459,
2005. Note: Erratum: J. Clin. Invest. 116: 549 only, 2006.
16. Tran, M. D.; Neary, J. T.: Purinergic signaling induces thrombospondin-1
expression in astrocytes. Proc. Nat. Acad. Sci. 103: 9321-9326,
2006.
17. Volpert, O. V.; Pili, R.; Sikder, H. A.; Nelius, T.; Zaichuk,
T.; Morris, C.; Shiflett, C. B.; Devlin, M. K.; Conant, K.; Alani,
R. M.: Id1 regulates angiogenesis through transcriptional repression
of thrombospondin-1. Cancer Cell 2: 473-483, 2002.
18. Volpert, O. V.; Zaichuk, T.; Zhou, W.; Reiher, F.; Ferguson, T.
A.; Stuart, P. M.; Amin, M.; Bouck, N. P.: Inducer-stimulated Fas
targets activated endothelium for destruction by anti-angiogenic thrombospondin-1
and pigment epithelium-derived factor. Nature Med. 8: 349-357, 2002.
19. Wolf, F. W.; Eddy, R. L.; Shows, T. B.; Dixit, V. M.: Structure
and chromosomal localization of the human thrombospondin gene. Genomics 6:
685-691, 1990.
*FIELD* CN
Marla J. F. O'Neill - updated: 6/10/2008
Patricia A. Hartz - updated: 5/1/2008
Patricia A. Hartz - updated: 10/4/2006
Patricia A. Hartz - updated: 7/28/2006
Patricia A. Hartz - updated: 2/2/2006
Patricia A. Hartz - updated: 1/12/2006
Patricia A. Hartz - updated: 10/13/2005
Stylianos E. Antonarakis - updated: 2/23/2005
Patricia A. Hartz - updated: 2/4/2003
Ada Hamosh - updated: 4/9/2002
Victor A. McKusick - updated: 1/11/2002
John A. Phillips, III - updated: 7/6/2001
Alan F. Scott - updated: 9/17/1995
*FIELD* CD
Victor A. McKusick: 10/16/1986
*FIELD* ED
terry: 11/28/2012
carol: 6/11/2008
terry: 6/10/2008
mgross: 5/1/2008
mgross: 7/25/2007
mgross: 10/4/2006
wwang: 8/8/2006
terry: 7/28/2006
mgross: 2/9/2006
terry: 2/2/2006
wwang: 1/12/2006
mgross: 10/13/2005
mgross: 2/23/2005
mgross: 2/4/2003
cwells: 4/17/2002
cwells: 4/15/2002
cwells: 4/12/2002
terry: 4/9/2002
carol: 1/20/2002
mcapotos: 1/11/2002
alopez: 7/6/2001
carol: 4/13/1998
terry: 3/30/1998
alopez: 6/3/1997
mark: 3/24/1997
mark: 9/18/1995
carol: 4/12/1994
carol: 3/19/1993
supermim: 3/16/1992
carol: 10/25/1991