Full text data of AKT1S1
AKT1S1
(PRAS40)
[Confidence: low (only semi-automatic identification from reviews)]
Proline-rich AKT1 substrate 1 (40 kDa proline-rich AKT substrate)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Proline-rich AKT1 substrate 1 (40 kDa proline-rich AKT substrate)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q96B36
ID AKTS1_HUMAN Reviewed; 256 AA.
AC Q96B36; A8MTQ1; B2RE93; J3KPM3; Q96BI4; Q96IK7; Q96NG2; Q9BWR5;
read moreDT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 93.
DE RecName: Full=Proline-rich AKT1 substrate 1;
DE AltName: Full=40 kDa proline-rich AKT substrate;
GN Name=AKT1S1; Synonyms=PRAS40;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Prostate, and Synovium;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Coronary artery;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (JUL-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP PRO-47.
RC TISSUE=Brain, Eye, and Skin;
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 INTERACTION WITH 14-3-3, TISSUE SPECIFICITY, AND PHOSPHORYLATION AT
RP THR-246.
RX PubMed=12524439; DOI=10.1074/jbc.M210837200;
RA Kovacina K.S., Park G.Y., Bae S.S., Guzzetta A.W., Schaefer E.,
RA Birnbaum M.J., Roth R.A.;
RT "Identification of a proline-rich Akt substrate as a 14-3-3 binding
RT partner.";
RL J. Biol. Chem. 278:10189-10194(2003).
RN [7]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16174443; DOI=10.1111/j.1745-7254.2005.00184.x;
RA Huang B., Porter G.;
RT "Expression of proline-rich Akt-substrate PRAS40 in cell survival
RT pathway and carcinogenesis.";
RL Acta Pharmacol. Sin. 26:1253-1258(2005).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-183, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP FUNCTION, IDENTIFICATION IN THE TORC1 COMPLEX, AND INTERACTION WITH
RP RPTOR.
RX PubMed=17386266; DOI=10.1016/j.molcel.2007.03.003;
RA Sancak Y., Thoreen C.C., Peterson T.R., Lindquist R.A., Kang S.A.,
RA Spooner E., Carr S.A., Sabatini D.M.;
RT "PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein
RT kinase.";
RL Mol. Cell 25:903-915(2007).
RN [10]
RP FUNCTION, IDENTIFICATION IN THE TORC1 COMPLEX, AND MUTAGENESIS OF
RP THR-246.
RX PubMed=17277771; DOI=10.1038/ncb1547;
RA Vander Haar E., Lee S.-I., Bandhakavi S., Griffin T.J., Kim D.-H.;
RT "Insulin signalling to mTOR mediated by the Akt/PKB substrate
RT PRAS40.";
RL Nat. Cell Biol. 9:316-323(2007).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88; SER-92; SER-183;
RP SER-202; SER-203; SER-211; SER-212 AND THR-246, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88; SER-92; SER-183;
RP SER-202; SER-211; SER-212 AND THR-246, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-183; SER-202; SER-203;
RP SER-211; SER-212 AND THR-246, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88; SER-92; SER-183 AND
RP THR-246, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
CC -!- FUNCTION: Subunit of mTORC1, which regulates cell growth and
CC survival in response to nutrient and hormonal signals. mTORC1 is
CC activated in response to growth factors or amino acids. Growth
CC factor-stimulated mTORC1 activation involves a AKT1-mediated
CC phosphorylation of TSC1-TSC2, which leads to the activation of the
CC RHEB GTPase that potently activates the protein kinase activity of
CC mTORC1. Amino acid-signaling to mTORC1 requires its relocalization
CC to the lysosomes mediated by the Ragulator complex and the Rag
CC GTPases. Activated mTORC1 up-regulates protein synthesis by
CC phosphorylating key regulators of mRNA translation and ribosome
CC synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from
CC inhibiting the elongation initiation factor 4E (eiF4E). mTORC1
CC phosphorylates and activates S6K1 at 'Thr-389', which then
CC promotes protein synthesis by phosphorylating PDCD4 and targeting
CC it for degradation. Within mTORC1, AKT1S1 negatively regulates
CC mTOR activity in a manner that is dependent on its phosphorylation
CC state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent
CC mTORC1 activation. Substrate for AKT1 phosphorylation, but can
CC also be activated by AKT1-independent mechanisms. May also play a
CC role in nerve growth factor-mediated neuroprotection.
CC -!- SUBUNIT: Part of the mammalian target of rapamycin complex 1
CC (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and
CC DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin.
CC Interacts directly with RPTOR. The phosphorylated form interacts
CC with 14-3-3 proteins.
CC -!- INTERACTION:
CC P29311:BMH1 (xeno); NbExp=3; IntAct=EBI-720593, EBI-3661;
CC Q04917:YWHAH; NbExp=3; IntAct=EBI-720593, EBI-306940;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol (By similarity).
CC Note=Found in the cytosolic fraction of the brain (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q96B36-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96B36-2; Sequence=VSP_052182;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q96B36-3; Sequence=VSP_047536;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels of
CC expression in liver and heart. Expressed at higher levels in
CC cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines
CC (e.g. HEK293).
CC -!- PTM: Phosphorylated by AKT1. Phosphorylation relieves inhibitory
CC function on mTORC1.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH00031.2; Type=Erroneous initiation;
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DR EMBL; AK055511; BAB70937.1; -; mRNA.
DR EMBL; AK092610; BAG52583.1; -; mRNA.
DR EMBL; AK316603; BAG38190.1; -; mRNA.
DR EMBL; AK226004; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC118341; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471177; EAW52570.1; -; Genomic_DNA.
DR EMBL; CH471177; EAW52568.1; -; Genomic_DNA.
DR EMBL; BC000031; AAH00031.2; ALT_INIT; mRNA.
DR EMBL; BC007416; AAH07416.1; -; mRNA.
DR EMBL; BC015562; AAH15562.1; -; mRNA.
DR EMBL; BC016043; AAH16043.1; -; mRNA.
DR EMBL; BC051844; AAH51844.1; -; mRNA.
DR RefSeq; NP_001092102.1; NM_001098632.2.
DR RefSeq; NP_001092103.1; NM_001098633.3.
DR RefSeq; NP_001265088.1; NM_001278159.1.
DR RefSeq; NP_001265089.1; NM_001278160.1.
DR RefSeq; NP_115751.3; NM_032375.5.
DR UniGene; Hs.515542; -.
DR UniGene; Hs.610819; -.
DR ProteinModelPortal; Q96B36; -.
DR IntAct; Q96B36; 11.
DR MINT; MINT-3317903; -.
DR STRING; 9606.ENSP00000341698; -.
DR BindingDB; Q96B36; -.
DR ChEMBL; CHEMBL1255161; -.
DR PhosphoSite; Q96B36; -.
DR DMDM; 74731194; -.
DR PaxDb; Q96B36; -.
DR PRIDE; Q96B36; -.
DR Ensembl; ENST00000344175; ENSP00000341698; ENSG00000204673.
DR Ensembl; ENST00000391831; ENSP00000375707; ENSG00000204673.
DR Ensembl; ENST00000391832; ENSP00000375708; ENSG00000204673.
DR Ensembl; ENST00000391833; ENSP00000375709; ENSG00000204673.
DR Ensembl; ENST00000391834; ENSP00000375710; ENSG00000204673.
DR Ensembl; ENST00000391835; ENSP00000375711; ENSG00000204673.
DR GeneID; 84335; -.
DR KEGG; hsa:84335; -.
DR UCSC; uc002pql.5; human.
DR CTD; 84335; -.
DR GeneCards; GC19M050372; -.
DR HGNC; HGNC:28426; AKT1S1.
DR HPA; CAB021903; -.
DR MIM; 610221; gene.
DR neXtProt; NX_Q96B36; -.
DR PharmGKB; PA134943587; -.
DR eggNOG; NOG40718; -.
DR HOVERGEN; HBG059465; -.
DR InParanoid; Q96B36; -.
DR KO; K16184; -.
DR OMA; CLHDIAQ; -.
DR OrthoDB; EOG7X3QRW; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q96B36; -.
DR ChiTaRS; AKT1S1; human.
DR GeneWiki; AKT1S1; -.
DR GenomeRNAi; 84335; -.
DR NextBio; 35535165; -.
DR PRO; PR:Q96B36; -.
DR ArrayExpress; Q96B36; -.
DR Bgee; Q96B36; -.
DR CleanEx; HS_AKT1S1; -.
DR Genevestigator; Q96B36; -.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0045792; P:negative regulation of cell size; IDA:UniProtKB.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IDA:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling cascade; IDA:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR InterPro; IPR026682; AKT1S1.
DR PANTHER; PTHR21844; PTHR21844; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Cytoplasm; Phosphoprotein;
KW Polymorphism; Reference proteome.
FT CHAIN 1 256 Proline-rich AKT1 substrate 1.
FT /FTId=PRO_0000253446.
FT COMPBIAS 35 43 Poly-Pro.
FT COMPBIAS 77 96 Pro-rich.
FT MOD_RES 88 88 Phosphoserine.
FT MOD_RES 92 92 Phosphoserine.
FT MOD_RES 183 183 Phosphoserine.
FT MOD_RES 202 202 Phosphoserine.
FT MOD_RES 203 203 Phosphoserine.
FT MOD_RES 211 211 Phosphoserine.
FT MOD_RES 212 212 Phosphoserine.
FT MOD_RES 246 246 Phosphothreonine; by PKB/AKT1.
FT VAR_SEQ 1 130 Missing (in isoform 2).
FT /FTId=VSP_052182.
FT VAR_SEQ 1 1 M -> MSFEGGDGAGPAMLATGTARM (in isoform
FT 3).
FT /FTId=VSP_047536.
FT VARIANT 47 47 A -> P (in dbSNP:rs17850191).
FT /FTId=VAR_028239.
FT MUTAGEN 246 246 T->A: Suppresses S6K1 phosphorylation by
FT mTORC1.
FT CONFLICT 108 108 D -> G (in Ref. 1; BAB70937).
FT CONFLICT 196 196 K -> M (in Ref. 1; BAB70937).
FT CONFLICT 233 233 T -> A (in Ref. 1; BAB70937).
SQ SEQUENCE 256 AA; 27383 MW; F6CB195CBB54326C CRC64;
MASGRPEELW EAVVGAAERF RARTGTELVL LTAAPPPPPR PGPCAYAAHG RGALAEAARR
CLHDIALAHR AATAARPPAP PPAPQPPSPT PSPPRPTLAR EDNEEDEDEP TETETSGEQL
GISDNGGLFV MDEDATLQDL PPFCESDPES TDDGSLSEET PAGPPTCSVP PASALPTQQY
AKSLPVSVPV WGFKEKRTEA RSSDEENGPP SSPDLDRIAA SMRALVLREA EDTQVFGDLP
RPRLNTSDFQ KLKRKY
//
ID AKTS1_HUMAN Reviewed; 256 AA.
AC Q96B36; A8MTQ1; B2RE93; J3KPM3; Q96BI4; Q96IK7; Q96NG2; Q9BWR5;
read moreDT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 93.
DE RecName: Full=Proline-rich AKT1 substrate 1;
DE AltName: Full=40 kDa proline-rich AKT substrate;
GN Name=AKT1S1; Synonyms=PRAS40;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Prostate, and Synovium;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Coronary artery;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (JUL-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP PRO-47.
RC TISSUE=Brain, Eye, and Skin;
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 INTERACTION WITH 14-3-3, TISSUE SPECIFICITY, AND PHOSPHORYLATION AT
RP THR-246.
RX PubMed=12524439; DOI=10.1074/jbc.M210837200;
RA Kovacina K.S., Park G.Y., Bae S.S., Guzzetta A.W., Schaefer E.,
RA Birnbaum M.J., Roth R.A.;
RT "Identification of a proline-rich Akt substrate as a 14-3-3 binding
RT partner.";
RL J. Biol. Chem. 278:10189-10194(2003).
RN [7]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16174443; DOI=10.1111/j.1745-7254.2005.00184.x;
RA Huang B., Porter G.;
RT "Expression of proline-rich Akt-substrate PRAS40 in cell survival
RT pathway and carcinogenesis.";
RL Acta Pharmacol. Sin. 26:1253-1258(2005).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-183, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP FUNCTION, IDENTIFICATION IN THE TORC1 COMPLEX, AND INTERACTION WITH
RP RPTOR.
RX PubMed=17386266; DOI=10.1016/j.molcel.2007.03.003;
RA Sancak Y., Thoreen C.C., Peterson T.R., Lindquist R.A., Kang S.A.,
RA Spooner E., Carr S.A., Sabatini D.M.;
RT "PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein
RT kinase.";
RL Mol. Cell 25:903-915(2007).
RN [10]
RP FUNCTION, IDENTIFICATION IN THE TORC1 COMPLEX, AND MUTAGENESIS OF
RP THR-246.
RX PubMed=17277771; DOI=10.1038/ncb1547;
RA Vander Haar E., Lee S.-I., Bandhakavi S., Griffin T.J., Kim D.-H.;
RT "Insulin signalling to mTOR mediated by the Akt/PKB substrate
RT PRAS40.";
RL Nat. Cell Biol. 9:316-323(2007).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88; SER-92; SER-183;
RP SER-202; SER-203; SER-211; SER-212 AND THR-246, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88; SER-92; SER-183;
RP SER-202; SER-211; SER-212 AND THR-246, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-183; SER-202; SER-203;
RP SER-211; SER-212 AND THR-246, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88; SER-92; SER-183 AND
RP THR-246, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
CC -!- FUNCTION: Subunit of mTORC1, which regulates cell growth and
CC survival in response to nutrient and hormonal signals. mTORC1 is
CC activated in response to growth factors or amino acids. Growth
CC factor-stimulated mTORC1 activation involves a AKT1-mediated
CC phosphorylation of TSC1-TSC2, which leads to the activation of the
CC RHEB GTPase that potently activates the protein kinase activity of
CC mTORC1. Amino acid-signaling to mTORC1 requires its relocalization
CC to the lysosomes mediated by the Ragulator complex and the Rag
CC GTPases. Activated mTORC1 up-regulates protein synthesis by
CC phosphorylating key regulators of mRNA translation and ribosome
CC synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from
CC inhibiting the elongation initiation factor 4E (eiF4E). mTORC1
CC phosphorylates and activates S6K1 at 'Thr-389', which then
CC promotes protein synthesis by phosphorylating PDCD4 and targeting
CC it for degradation. Within mTORC1, AKT1S1 negatively regulates
CC mTOR activity in a manner that is dependent on its phosphorylation
CC state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent
CC mTORC1 activation. Substrate for AKT1 phosphorylation, but can
CC also be activated by AKT1-independent mechanisms. May also play a
CC role in nerve growth factor-mediated neuroprotection.
CC -!- SUBUNIT: Part of the mammalian target of rapamycin complex 1
CC (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and
CC DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin.
CC Interacts directly with RPTOR. The phosphorylated form interacts
CC with 14-3-3 proteins.
CC -!- INTERACTION:
CC P29311:BMH1 (xeno); NbExp=3; IntAct=EBI-720593, EBI-3661;
CC Q04917:YWHAH; NbExp=3; IntAct=EBI-720593, EBI-306940;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol (By similarity).
CC Note=Found in the cytosolic fraction of the brain (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q96B36-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96B36-2; Sequence=VSP_052182;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q96B36-3; Sequence=VSP_047536;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels of
CC expression in liver and heart. Expressed at higher levels in
CC cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines
CC (e.g. HEK293).
CC -!- PTM: Phosphorylated by AKT1. Phosphorylation relieves inhibitory
CC function on mTORC1.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH00031.2; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AK055511; BAB70937.1; -; mRNA.
DR EMBL; AK092610; BAG52583.1; -; mRNA.
DR EMBL; AK316603; BAG38190.1; -; mRNA.
DR EMBL; AK226004; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC118341; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471177; EAW52570.1; -; Genomic_DNA.
DR EMBL; CH471177; EAW52568.1; -; Genomic_DNA.
DR EMBL; BC000031; AAH00031.2; ALT_INIT; mRNA.
DR EMBL; BC007416; AAH07416.1; -; mRNA.
DR EMBL; BC015562; AAH15562.1; -; mRNA.
DR EMBL; BC016043; AAH16043.1; -; mRNA.
DR EMBL; BC051844; AAH51844.1; -; mRNA.
DR RefSeq; NP_001092102.1; NM_001098632.2.
DR RefSeq; NP_001092103.1; NM_001098633.3.
DR RefSeq; NP_001265088.1; NM_001278159.1.
DR RefSeq; NP_001265089.1; NM_001278160.1.
DR RefSeq; NP_115751.3; NM_032375.5.
DR UniGene; Hs.515542; -.
DR UniGene; Hs.610819; -.
DR ProteinModelPortal; Q96B36; -.
DR IntAct; Q96B36; 11.
DR MINT; MINT-3317903; -.
DR STRING; 9606.ENSP00000341698; -.
DR BindingDB; Q96B36; -.
DR ChEMBL; CHEMBL1255161; -.
DR PhosphoSite; Q96B36; -.
DR DMDM; 74731194; -.
DR PaxDb; Q96B36; -.
DR PRIDE; Q96B36; -.
DR Ensembl; ENST00000344175; ENSP00000341698; ENSG00000204673.
DR Ensembl; ENST00000391831; ENSP00000375707; ENSG00000204673.
DR Ensembl; ENST00000391832; ENSP00000375708; ENSG00000204673.
DR Ensembl; ENST00000391833; ENSP00000375709; ENSG00000204673.
DR Ensembl; ENST00000391834; ENSP00000375710; ENSG00000204673.
DR Ensembl; ENST00000391835; ENSP00000375711; ENSG00000204673.
DR GeneID; 84335; -.
DR KEGG; hsa:84335; -.
DR UCSC; uc002pql.5; human.
DR CTD; 84335; -.
DR GeneCards; GC19M050372; -.
DR HGNC; HGNC:28426; AKT1S1.
DR HPA; CAB021903; -.
DR MIM; 610221; gene.
DR neXtProt; NX_Q96B36; -.
DR PharmGKB; PA134943587; -.
DR eggNOG; NOG40718; -.
DR HOVERGEN; HBG059465; -.
DR InParanoid; Q96B36; -.
DR KO; K16184; -.
DR OMA; CLHDIAQ; -.
DR OrthoDB; EOG7X3QRW; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q96B36; -.
DR ChiTaRS; AKT1S1; human.
DR GeneWiki; AKT1S1; -.
DR GenomeRNAi; 84335; -.
DR NextBio; 35535165; -.
DR PRO; PR:Q96B36; -.
DR ArrayExpress; Q96B36; -.
DR Bgee; Q96B36; -.
DR CleanEx; HS_AKT1S1; -.
DR Genevestigator; Q96B36; -.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0045792; P:negative regulation of cell size; IDA:UniProtKB.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IDA:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling cascade; IDA:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR InterPro; IPR026682; AKT1S1.
DR PANTHER; PTHR21844; PTHR21844; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Cytoplasm; Phosphoprotein;
KW Polymorphism; Reference proteome.
FT CHAIN 1 256 Proline-rich AKT1 substrate 1.
FT /FTId=PRO_0000253446.
FT COMPBIAS 35 43 Poly-Pro.
FT COMPBIAS 77 96 Pro-rich.
FT MOD_RES 88 88 Phosphoserine.
FT MOD_RES 92 92 Phosphoserine.
FT MOD_RES 183 183 Phosphoserine.
FT MOD_RES 202 202 Phosphoserine.
FT MOD_RES 203 203 Phosphoserine.
FT MOD_RES 211 211 Phosphoserine.
FT MOD_RES 212 212 Phosphoserine.
FT MOD_RES 246 246 Phosphothreonine; by PKB/AKT1.
FT VAR_SEQ 1 130 Missing (in isoform 2).
FT /FTId=VSP_052182.
FT VAR_SEQ 1 1 M -> MSFEGGDGAGPAMLATGTARM (in isoform
FT 3).
FT /FTId=VSP_047536.
FT VARIANT 47 47 A -> P (in dbSNP:rs17850191).
FT /FTId=VAR_028239.
FT MUTAGEN 246 246 T->A: Suppresses S6K1 phosphorylation by
FT mTORC1.
FT CONFLICT 108 108 D -> G (in Ref. 1; BAB70937).
FT CONFLICT 196 196 K -> M (in Ref. 1; BAB70937).
FT CONFLICT 233 233 T -> A (in Ref. 1; BAB70937).
SQ SEQUENCE 256 AA; 27383 MW; F6CB195CBB54326C CRC64;
MASGRPEELW EAVVGAAERF RARTGTELVL LTAAPPPPPR PGPCAYAAHG RGALAEAARR
CLHDIALAHR AATAARPPAP PPAPQPPSPT PSPPRPTLAR EDNEEDEDEP TETETSGEQL
GISDNGGLFV MDEDATLQDL PPFCESDPES TDDGSLSEET PAGPPTCSVP PASALPTQQY
AKSLPVSVPV WGFKEKRTEA RSSDEENGPP SSPDLDRIAA SMRALVLREA EDTQVFGDLP
RPRLNTSDFQ KLKRKY
//
MIM
610221
*RECORD*
*FIELD* NO
610221
*FIELD* TI
*610221 AKT1 SUBSTRATE 1, PROLINE-RICH; AKT1S1
;;PROLINE-RICH AKT SUBSTRATE, 40-KD; PRAS40;;
read moreMGC2865
*FIELD* TX
DESCRIPTION
AKT1S1 is a proline-rich substrate of AKT (164730) that binds 14-3-3
protein (see YWHAH, 113508) when phosphorylated (Kovacina et al., 2003).
CLONING
Kovacina et al. (2003) isolated a novel Akt substrate and 14-3-3-binding
protein, Akt1s1, which they called Pras40, from rat hepatoma cells. By
EST database analysis, they identified mouse and human PRAS40. The
deduced 256-amino acid human protein contains 2 N-terminal proline-rich
regions and a C-terminal AKT phosphorylation site, thr246, that is
conserved in rat and mouse. Northern blot analysis detected 2.6- and
1.8-kb PRAS40 transcripts in all tissues examined, with highest levels
of both transcripts in liver and heart. EST database analysis suggested
that these 2 transcripts are splice variants with identical coding
regions.
GENE FUNCTION
By in vitro analysis of AKT phosphorylation of PRAS40 expressed in E.
coli or HEK293 cells, Kovacina et al. (2003) confirmed that PRAS40 is a
substrate for AKT phosphorylation. Additional transfection of HEK293
cells with a constitutively active form of AKT increased PRAS40
phosphorylation. Phosphorylation induced by constitutively active AKT
was not blocked by a PI3K/AKT inhibitor, unlike that induced by wildtype
AKT. Mutation analysis showed that phosphorylation of PRAS40 by AKT
occurred at thr246. PRAS40 and 14-3-3 protein coimmunoprecipitated in
transfected HEK293 cells. Far Western blot analysis showed that 14-3-3
bound endogenous PRAS40 in a prostate cancer cell line, and, using a
reversible PI3K inhibitor, Kovacina et al. (2003) demonstrated that this
binding was regulated by phosphorylation of PRAS40.
Saito et al. (2004) showed that expression levels of phosphorylated
mouse Pras40, phosphorylated Pras40 bound to phosphorylated Akt, and
phosphorylated Pras40 bound to 14-3-3 protein all decreased in mouse
brains after experimentally-induced transient focal cerebral ischemia
(tFCI). Mouse brain cells overexpressing transfected human PRAS40
displayed decreased apoptotic neuronal cell death as measured by TUNEL
analysis of DNA fragmentation. Saito et al. (2004) suggested that PRAS40
may play a role in NGF (162030)-mediated neuroprotection.
Using immunoprecipitation analysis, Sancak et al. (2007) identified
PRAS40 as a raptor (607130)-interacting protein that bound to MTOR
(FRAP1; 601231) complex-1 (MTORC1) in insulin-deprived human embryonic
kidney cells. PRAS40 inhibited cell growth, S6K1 (RPS6KB1; 608938)
phosphorylation, and RHEB (601293)-induced activation of the MTORC1
pathway. In human embryonic kidney cells, it prevented the increase in
MTORC1 kinase activity induced by RHEB-GTP. Insulin stimulated
AKT-mediated phosphorylation of PRAS40, which prevented its inhibition
of MTORC1.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the AKT1S1
gene to chromosome 19 (TMAP RH36488).
*FIELD* RF
1. Kovacina, K. S.; Park, G. Y.; Bae, S. S.; Guzzetta, A. W.; Schaefer,
E.; Birnbaum, M. J.; Roth, R. A.: Identification of a proline-rich
Akt substrate as a 14-3-3 binding partner. J. Biol. Chem. 278: 10189-10194,
2003.
2. Saito, A.; Narasimhan, P.; Hayashi, T.; Okuno, S.; Ferrand-Drake,
M.; Chan, P. H.: Neuroprotective role of a proline-rich Akt substrate
in apoptotic neuronal cell death after stroke: relationships with
nerve growth factor. J. Neurosci. 24: 1584-1593, 2004.
3. Sancak, Y.; Thoreen, C. C.; Peterson, T. R.; Lindquist, R. A.;
Kang, S. A.; Spooner, E.; Carr, S. A.; Sabatini, D. M.: PRAS40 is
an insulin-regulated inhibitor of the mTORC1 protein kinase. Molec.
Cell 25: 903-915, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 5/8/2007
*FIELD* CD
Dorothy S. Reilly: 6/29/2006
*FIELD* ED
mgross: 05/30/2007
terry: 5/8/2007
wwang: 7/5/2006
wwang: 6/29/2006
*RECORD*
*FIELD* NO
610221
*FIELD* TI
*610221 AKT1 SUBSTRATE 1, PROLINE-RICH; AKT1S1
;;PROLINE-RICH AKT SUBSTRATE, 40-KD; PRAS40;;
read moreMGC2865
*FIELD* TX
DESCRIPTION
AKT1S1 is a proline-rich substrate of AKT (164730) that binds 14-3-3
protein (see YWHAH, 113508) when phosphorylated (Kovacina et al., 2003).
CLONING
Kovacina et al. (2003) isolated a novel Akt substrate and 14-3-3-binding
protein, Akt1s1, which they called Pras40, from rat hepatoma cells. By
EST database analysis, they identified mouse and human PRAS40. The
deduced 256-amino acid human protein contains 2 N-terminal proline-rich
regions and a C-terminal AKT phosphorylation site, thr246, that is
conserved in rat and mouse. Northern blot analysis detected 2.6- and
1.8-kb PRAS40 transcripts in all tissues examined, with highest levels
of both transcripts in liver and heart. EST database analysis suggested
that these 2 transcripts are splice variants with identical coding
regions.
GENE FUNCTION
By in vitro analysis of AKT phosphorylation of PRAS40 expressed in E.
coli or HEK293 cells, Kovacina et al. (2003) confirmed that PRAS40 is a
substrate for AKT phosphorylation. Additional transfection of HEK293
cells with a constitutively active form of AKT increased PRAS40
phosphorylation. Phosphorylation induced by constitutively active AKT
was not blocked by a PI3K/AKT inhibitor, unlike that induced by wildtype
AKT. Mutation analysis showed that phosphorylation of PRAS40 by AKT
occurred at thr246. PRAS40 and 14-3-3 protein coimmunoprecipitated in
transfected HEK293 cells. Far Western blot analysis showed that 14-3-3
bound endogenous PRAS40 in a prostate cancer cell line, and, using a
reversible PI3K inhibitor, Kovacina et al. (2003) demonstrated that this
binding was regulated by phosphorylation of PRAS40.
Saito et al. (2004) showed that expression levels of phosphorylated
mouse Pras40, phosphorylated Pras40 bound to phosphorylated Akt, and
phosphorylated Pras40 bound to 14-3-3 protein all decreased in mouse
brains after experimentally-induced transient focal cerebral ischemia
(tFCI). Mouse brain cells overexpressing transfected human PRAS40
displayed decreased apoptotic neuronal cell death as measured by TUNEL
analysis of DNA fragmentation. Saito et al. (2004) suggested that PRAS40
may play a role in NGF (162030)-mediated neuroprotection.
Using immunoprecipitation analysis, Sancak et al. (2007) identified
PRAS40 as a raptor (607130)-interacting protein that bound to MTOR
(FRAP1; 601231) complex-1 (MTORC1) in insulin-deprived human embryonic
kidney cells. PRAS40 inhibited cell growth, S6K1 (RPS6KB1; 608938)
phosphorylation, and RHEB (601293)-induced activation of the MTORC1
pathway. In human embryonic kidney cells, it prevented the increase in
MTORC1 kinase activity induced by RHEB-GTP. Insulin stimulated
AKT-mediated phosphorylation of PRAS40, which prevented its inhibition
of MTORC1.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the AKT1S1
gene to chromosome 19 (TMAP RH36488).
*FIELD* RF
1. Kovacina, K. S.; Park, G. Y.; Bae, S. S.; Guzzetta, A. W.; Schaefer,
E.; Birnbaum, M. J.; Roth, R. A.: Identification of a proline-rich
Akt substrate as a 14-3-3 binding partner. J. Biol. Chem. 278: 10189-10194,
2003.
2. Saito, A.; Narasimhan, P.; Hayashi, T.; Okuno, S.; Ferrand-Drake,
M.; Chan, P. H.: Neuroprotective role of a proline-rich Akt substrate
in apoptotic neuronal cell death after stroke: relationships with
nerve growth factor. J. Neurosci. 24: 1584-1593, 2004.
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*FIELD* CN
Patricia A. Hartz - updated: 5/8/2007
*FIELD* CD
Dorothy S. Reilly: 6/29/2006
*FIELD* ED
mgross: 05/30/2007
terry: 5/8/2007
wwang: 7/5/2006
wwang: 6/29/2006