Full text data of KALRN
KALRN
(DUET, DUO, HAPIP, TRAD)
[Confidence: low (only semi-automatic identification from reviews)]
Kalirin; 2.7.11.1 (Huntingtin-associated protein-interacting protein; Protein Duo; Serine/threonine-protein kinase with Dbl- and pleckstrin homology domain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Kalirin; 2.7.11.1 (Huntingtin-associated protein-interacting protein; Protein Duo; Serine/threonine-protein kinase with Dbl- and pleckstrin homology domain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
O60229
ID KALRN_HUMAN Reviewed; 2985 AA.
AC O60229; A8MSI4; C9JQ37; Q6ZN45; Q8TBQ5; Q9NSZ4; Q9Y2A5;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-OCT-2007, sequence version 2.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=Kalirin;
DE EC=2.7.11.1;
DE AltName: Full=Huntingtin-associated protein-interacting protein;
DE AltName: Full=Protein Duo;
DE AltName: Full=Serine/threonine-protein kinase with Dbl- and pleckstrin homology domain;
GN Name=KALRN; Synonyms=DUET, DUO, HAPIP, TRAD;
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] (ISOFORM 2).
RC TISSUE=Frontal cortex;
RX PubMed=9285789; DOI=10.1093/hmg/6.9.1519;
RA Colomer V., Engelender S., Sharp A.H., Duan K., Cooper J.K.,
RA Lanahan A., Lyford G., Worley P., Ross C.A.;
RT "Huntingtin-associated protein 1 (HAP1) binds to a Trio-like
RT polypeptide, with a rac1 guanine nucleotide exchange factor domain.";
RL Hum. Mol. Genet. 6:1519-1525(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), FUNCTION, MUTAGENESIS OF
RP LYS-2712, AUTOPHOSPHORYLATION, TISSUE SPECIFICITY, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Skeletal muscle;
RX PubMed=10023074; DOI=10.1016/S0378-1119(98)00605-2;
RA Kawai T., Sanjo H., Akira S.;
RT "Duet is a novel serine/threonine kinase with Dbl-homology (DH) and
RT pleckstrin-homology (PH) domains.";
RL Gene 227:249-255(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 5).
RC TISSUE=Amygdala, and Testis;
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=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1917 (ISOFORM 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2104-2985 (ISOFORM 5).
RC TISSUE=Kidney;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2016-2985 (ISOFORM 5).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP INVOLVEMENT IN CHDS5.
RX PubMed=17357071; DOI=10.1086/512981;
RA Wang L., Hauser E.R., Shah S.H., Pericak-Vance M.A., Haynes C.,
RA Crosslin D., Harris M. II, Nelson S., Hale A.B., Granger C.B.,
RA Haines J.L., Jones C.J.H., Crossman D., Seo D., Gregory S.G.,
RA Kraus W.E., Goldschmidt-Clermont P.J., Vance J.M.;
RT "Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a
RT novel candidate gene for coronary artery disease.";
RL Am. J. Hum. Genet. 80:650-663(2007).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1750; SER-1753;
RP SER-1799; SER-1817 AND SER-2261, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1799, AND MASS
RP 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 [11]
RP INTERACTION WITH FASLG.
RX PubMed=19807924; DOI=10.1186/1471-2172-10-53;
RA Voss M., Lettau M., Janssen O.;
RT "Identification of SH3 domain interaction partners of human FasL
RT (CD178) by phage display screening.";
RL BMC Immunol. 10:53-53(2009).
RN [12]
RP VARIANTS [LARGE SCALE ANALYSIS] TRP-213 AND CYS-1896.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [13]
RP VARIANT [LARGE SCALE ANALYSIS] LEU-196.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Promotes the exchange of GDP by GTP. Activates specific
CC Rho GTPase family members, thereby inducing various signaling
CC mechanisms that regulate neuronal shape, growth, and plasticity,
CC through their effects on the actin cytoskeleton. Induces
CC lamellipodia independent of its GEF activity.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- SUBUNIT: Interacts with the C-terminal of peptidylglycine alpha-
CC amidating monooxygenase (PAM) and with the huntingtin-associated
CC protein 1 (HAP1) (By similarity). Interacts with FASLG.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cytoskeleton.
CC Note=Associated with the cytoskeleton.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=6;
CC Name=1;
CC IsoId=O60229-1; Sequence=Displayed;
CC Note=Produced by alternative splicing;
CC Name=2;
CC IsoId=O60229-2; Sequence=VSP_028910, VSP_028911;
CC Note=Produced by alternative splicing. No experimental
CC confirmation available;
CC Name=3;
CC IsoId=O60229-3; Sequence=VSP_028905, VSP_028906, VSP_028907,
CC VSP_028908;
CC Note=Produced by alternative initiation at Met-624 of isoform 1.
CC Inferred by similarity;
CC Name=4; Synonyms=DUET, TRAD;
CC IsoId=O60229-4; Sequence=VSP_028903, VSP_028912, VSP_047353;
CC Note=Produced by alternative splicing;
CC Name=5;
CC IsoId=O60229-5; Sequence=VSP_028904, VSP_028909, VSP_028913,
CC VSP_028914, VSP_028915;
CC Note=Produced by alternative splicing;
CC Name=6;
CC IsoId=O60229-6; Sequence=VSP_028903, VSP_028912, VSP_028913;
CC Note=Produced by alternative splicing. No experimental
CC confirmation available;
CC -!- TISSUE SPECIFICITY: Isoform 2 is brain specific. Highly expressed
CC in cerebral cortex, putamen, amygdala, hippocampus and caudate
CC nucleus. Weakly expressed in brain stem and cerebellum. Isoform 4
CC is expressed in skeletal muscle.
CC -!- DOMAIN: The two GEF domains catalyze nucleotide exchange for RAC1
CC and RhoA which are bound by DH1 and DH2 respectively. The two GEF
CC domains appear to play differing roles in neuronal development and
CC axonal outgrowth. SH3 1 binds to the first GEF domain inhibiting
CC GEF activity only when in the presence of a PXXP peptide,
CC suggesting that the SH3 domain/peptide interaction mediates
CC binding to GEF1. CRK1 SH3 domain binds to and inhibits GEF1
CC activity (By similarity).
CC -!- PTM: Autophosphorylated.
CC -!- DISEASE: Coronary heart disease 5 (CHDS5) [MIM:608901]: A
CC multifactorial disease characterized by an imbalance between
CC myocardial functional requirements and the capacity of the
CC coronary vessels to supply sufficient blood flow. Decreased
CC capacity of the coronary vessels is often associated with
CC thickening and loss of elasticity of the coronary arteries.
CC Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Called DUO because the encoded protein is closely
CC related to but shorter than TRIO.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
CC Ser/Thr protein kinase family.
CC -!- SIMILARITY: Contains 1 CRAL-TRIO domain.
CC -!- SIMILARITY: Contains 2 DH (DBL-homology) domains.
CC -!- SIMILARITY: Contains 1 fibronectin type-III domain.
CC -!- SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like)
CC domain.
CC -!- SIMILARITY: Contains 2 PH domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 2 SH3 domains.
CC -!- SIMILARITY: Contains 5 spectrin repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH58015.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence;
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DR EMBL; U94190; AAC15791.1; -; mRNA.
DR EMBL; AB011422; BAA76314.1; -; mRNA.
DR EMBL; AK125979; BAC86373.1; -; mRNA.
DR EMBL; AK131379; BAD18530.1; -; mRNA.
DR EMBL; AC022336; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC069233; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC080008; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC112129; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC117401; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW79410.1; -; Genomic_DNA.
DR EMBL; BC026865; AAH26865.1; -; mRNA.
DR EMBL; BC058015; AAH58015.1; ALT_SEQ; mRNA.
DR EMBL; AL137629; CAB70850.1; -; mRNA.
DR PIR; T46482; T46482.
DR RefSeq; NP_001019831.2; NM_001024660.3.
DR RefSeq; NP_003938.1; NM_003947.4.
DR RefSeq; NP_008995.2; NM_007064.3.
DR UniGene; Hs.8004; -.
DR ProteinModelPortal; O60229; -.
DR SMR; O60229; 1279-1582, 1645-1711, 1918-2247, 2324-2389.
DR IntAct; O60229; 9.
DR MINT; MINT-2865643; -.
DR STRING; 9606.ENSP00000240874; -.
DR PhosphoSite; O60229; -.
DR PaxDb; O60229; -.
DR PRIDE; O60229; -.
DR DNASU; 8997; -.
DR Ensembl; ENST00000240874; ENSP00000240874; ENSG00000160145.
DR Ensembl; ENST00000291478; ENSP00000291478; ENSG00000160145.
DR Ensembl; ENST00000393496; ENSP00000377134; ENSG00000160145.
DR Ensembl; ENST00000428018; ENSP00000402419; ENSG00000160145.
DR GeneID; 8997; -.
DR KEGG; hsa:8997; -.
DR UCSC; uc003ehk.3; human.
DR CTD; 8997; -.
DR GeneCards; GC03P123798; -.
DR HGNC; HGNC:4814; KALRN.
DR HPA; CAB026456; -.
DR HPA; HPA011913; -.
DR MIM; 604605; gene.
DR MIM; 608901; phenotype.
DR neXtProt; NX_O60229; -.
DR PharmGKB; PA29189; -.
DR eggNOG; NOG331990; -.
DR HOGENOM; HOG000044462; -.
DR HOVERGEN; HBG108598; -.
DR InParanoid; O60229; -.
DR KO; K15048; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; O60229; -.
DR ChiTaRS; KALRN; human.
DR GeneWiki; Kalirin; -.
DR GenomeRNAi; 8997; -.
DR NextBio; 33739; -.
DR PRO; PR:O60229; -.
DR ArrayExpress; O60229; -.
DR Bgee; O60229; -.
DR CleanEx; HS_KALRN; -.
DR Genevestigator; O60229; -.
DR GO; GO:0015629; C:actin cytoskeleton; TAS:ProtInc.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:ProtInc.
DR GO; GO:0005089; F:Rho guanyl-nucleotide exchange factor activity; IEA:InterPro.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0007399; P:nervous system development; ISS:HGNC.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0016192; P:vesicle-mediated transport; TAS:ProtInc.
DR Gene3D; 1.20.900.10; -; 2.
DR Gene3D; 2.30.29.30; -; 2.
DR Gene3D; 2.60.40.10; -; 2.
DR Gene3D; 3.40.525.10; -; 1.
DR InterPro; IPR001251; CRAL-TRIO_dom.
DR InterPro; IPR000219; DH-domain.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR028569; Kalirin.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR001452; SH3_domain.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR InterPro; IPR002017; Spectrin_repeat.
DR PANTHER; PTHR22826:SF49; PTHR22826:SF49; 1.
DR Pfam; PF13716; CRAL_TRIO_2; 1.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF07679; I-set; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00621; RhoGEF; 2.
DR Pfam; PF00435; Spectrin; 4.
DR SMART; SM00060; FN3; 1.
DR SMART; SM00408; IGc2; 1.
DR SMART; SM00233; PH; 2.
DR SMART; SM00325; RhoGEF; 2.
DR SMART; SM00220; S_TKc; 1.
DR SMART; SM00516; SEC14; 1.
DR SMART; SM00326; SH3; 2.
DR SMART; SM00150; SPEC; 7.
DR SUPFAM; SSF48065; SSF48065; 2.
DR SUPFAM; SSF49265; SSF49265; 1.
DR SUPFAM; SSF50044; SSF50044; 2.
DR SUPFAM; SSF52087; SSF52087; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50191; CRAL_TRIO; 1.
DR PROSITE; PS00741; DH_1; FALSE_NEG.
DR PROSITE; PS50010; DH_2; 2.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
DR PROSITE; PS50003; PH_DOMAIN; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Cytoskeleton; Disulfide bond;
KW Guanine-nucleotide releasing factor; Immunoglobulin domain; Kinase;
KW Magnesium; Metal-binding; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; SH3 domain; Transferase.
FT CHAIN 1 2985 Kalirin.
FT /FTId=PRO_0000080955.
FT DOMAIN 35 180 CRAL-TRIO.
FT REPEAT 188 308 Spectrin 1.
FT REPEAT 310 416 Spectrin 2.
FT REPEAT 536 642 Spectrin 3.
FT REPEAT 890 1004 Spectrin 4.
FT REPEAT 1130 1222 Spectrin 5.
FT DOMAIN 1281 1456 DH 1.
FT DOMAIN 1468 1580 PH 1.
FT DOMAIN 1646 1711 SH3 1.
FT DOMAIN 1928 2103 DH 2.
FT DOMAIN 2115 2225 PH 2.
FT DOMAIN 2320 2385 SH3 2.
FT DOMAIN 2470 2563 Ig-like C2-type.
FT DOMAIN 2570 2664 Fibronectin type-III.
FT DOMAIN 2683 2937 Protein kinase.
FT NP_BIND 2689 2697 ATP (By similarity).
FT COMPBIAS 682 687 Poly-Gln.
FT ACT_SITE 2802 2802 Proton acceptor (By similarity).
FT BINDING 2712 2712 ATP.
FT MOD_RES 1750 1750 Phosphoserine.
FT MOD_RES 1753 1753 Phosphoserine.
FT MOD_RES 1799 1799 Phosphoserine.
FT MOD_RES 1817 1817 Phosphoserine.
FT MOD_RES 2261 2261 Phosphoserine.
FT DISULFID 2491 2547 By similarity.
FT VAR_SEQ 1 1697 Missing (in isoform 4 and isoform 6).
FT /FTId=VSP_028903.
FT VAR_SEQ 1 1627 Missing (in isoform 5).
FT /FTId=VSP_028904.
FT VAR_SEQ 1 641 Missing (in isoform 3).
FT /FTId=VSP_028905.
FT VAR_SEQ 709 721 Missing (in isoform 3).
FT /FTId=VSP_028906.
FT VAR_SEQ 1465 1505 FDENLDVQGELILQDAFQVWDPKSLIRKGRERHLFLFEISL
FT -> SCPPSTGEASSLPRHGGACIMGGKWHEVRQGARLEERR
FT NDK (in isoform 3).
FT /FTId=VSP_028907.
FT VAR_SEQ 1506 2985 Missing (in isoform 3).
FT /FTId=VSP_028908.
FT VAR_SEQ 1628 1643 ISIASRTSQNTVDSDK -> MLKWISWRQSKANKAQ (in
FT isoform 5).
FT /FTId=VSP_028909.
FT VAR_SEQ 1644 1663 LSGGCELTVVLQDFSAGHSS -> DGNLVPRWHLGPGDPFS
FT TYV (in isoform 2).
FT /FTId=VSP_028910.
FT VAR_SEQ 1664 2985 Missing (in isoform 2).
FT /FTId=VSP_028911.
FT VAR_SEQ 1698 1725 EGLVPSSALCISHSRSSVEMDCFFPLVK -> MKGGDRAYT
FT RGPSLGWLFAKCCCCFPCR (in isoform 4 and
FT isoform 6).
FT /FTId=VSP_028912.
FT VAR_SEQ 1857 1887 Missing (in isoform 5 and isoform 6).
FT /FTId=VSP_028913.
FT VAR_SEQ 1857 1857 S -> SS (in isoform 4).
FT /FTId=VSP_047353.
FT VAR_SEQ 2313 2313 Missing (in isoform 5).
FT /FTId=VSP_028914.
FT VAR_SEQ 2398 2985 Missing (in isoform 5).
FT /FTId=VSP_028915.
FT VARIANT 196 196 S -> L.
FT /FTId=VAR_041898.
FT VARIANT 213 213 R -> W (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035976.
FT VARIANT 1326 1326 E -> D (in dbSNP:rs2289838).
FT /FTId=VAR_020192.
FT VARIANT 1896 1896 S -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035625.
FT VARIANT 1929 1929 R -> M (in dbSNP:rs35298864).
FT /FTId=VAR_057190.
FT MUTAGEN 2712 2712 K->A: Loss of autophosphorylation.
FT CONFLICT 2458 2458 E -> G (in Ref. 2; BAA76314).
SQ SEQUENCE 2985 AA; 340174 MW; F4C01D0F2422A92F CRC64;
MTDRFWDQWY LWYLRLLRLL DRGSFRNDGL KASDVLPILK EKVAFVSGGR DKRGGPILTF
PARSNHDRIR QEDLRKLVTY LASVPSEDVC KRGFTVIIDM RGSKWDLIKP LLKTLQEAFP
AEIHVALIIK PDNFWQKQKT NFGSSKFIFE TSMVSVEGLT KLVDPSQLTE EFDGSLDYNH
EEWIELRLSL EEFFNSAVHL LSRLEDLQEM LARKEFPVDV EGSRRLIDEH TQLKKKVLKA
PVEELDREGQ RLLQCIRCSD GFSGRNCIPG SADFQSLVPK ITSLLDKLHS TRQHLHQMWH
VRKLKLDQCF QLRLFEQDAE KMFDWISHNK ELFLQSHTEI GVSYQYALDL QTQHNHFAMN
SMNAYVNINR IMSVASRLSE AGHYASQQIK QISTQLDQEW KSFAAALDER STILAMSAVF
HQKAEQFLSG VDAWCKMCSE GGLPSEMQDL ELAIHHHQTL YEQVTQAYTE VSQDGKALLD
VLQRPLSPGN SESLTATANY SKAVHQVLDV VHEVLHHQRR LESIWQHRKV RLHQRLQLCV
FQQDVQQVLD WIENHGEAFL SKHTGVGKSL HRARALQKRH DDFEEVAQNT YTNADKLLEA
AEQLAQTGEC DPEEIYKAAR HLEVRIQDFV RRVEQRKLLL DMSVSFHTHT KELWTWMEDL
QKEMLEDVCA DSVDAVQELI KQFQQQQTAT LDATLNVIKE GEDLIQQLRS APPSLGEPSE
ARDSAVSNNK TPHSSSISHI ESVLQQLDDA QVQMEELFHE RKIKLDIFLQ LRIFEQYTIE
VTAELDAWNE DLLRQMNDFN TEDLTLAEQR LQRHTERKLA MNNMTFEVIQ QGQDLHQYIT
EVQASGIELI CEKDIDLAAQ VQELLEFLHE KQHELELNAE QTHKRLEQCL QLRHLQAEVK
QVLGWIRNGE SMLNASLVNA SSLSEAEQLQ REHEQFQLAI ESLFHATSLQ KTHQSALQVQ
QKAEVLLQAG HYDADAIREC AEKVALHWQQ LMLKMEDRLK LVNASVAFYK TSEQVCSVLE
SLEQEYRRDE DWCGGRDKLG PAAEIDHVIP LISKHLEQKE AFLKACTLAR RNAEVFLKYI
HRNNVSMPSV ASHTRGPEQQ VKAILSELLQ RENRVLHFWT LKKRRLDQCQ QYVVFERSAK
QALDWIQETG EFYLSTHTST GETTEETQEL LKEYGEFRVP AKQTKEKVKL LIQLADSFVE
KGHIHATEIR KWVTTVDKHY RDFSLRMGKY RYSLEKALGV NTEDNKDLEL DIIPASLSDR
EVKLRDANHE VNEEKRKSAR KKEFIMAELL QTEKAYVRDL HECLETYLWE MTSGVEEIPP
GILNKEHIIF GNIQEIYDFH NNIFLKELEK YEQLPEDVGH CFVTWADKFQ MYVTYCKNKP
DSNQLILEHA GTFFDEIQQR HGLANSISSY LIKPVQRITK YQLLLKELLT CCEEGKGELK
DGLEVMLSVP KKANDAMHVS MLEGFDENLD VQGELILQDA FQVWDPKSLI RKGRERHLFL
FEISLVFSKE IKDSSGHTKY VYKNKLLTSE LGVTEHVEGD PCKFALWSGR TPSSDNKTVL
KASNIETKQE WIKNIREVIQ ERIIHLKGAL KEPLQLPKTP AKQRNNSKRD GVEDIDSQGD
GSSQPDTISI ASRTSQNTVD SDKLSGGCEL TVVLQDFSAG HSSELTIQVG QTVELLERPS
ERPGWCLVRT TERSPPLEGL VPSSALCISH SRSSVEMDCF FPLVKDAYSH SSSENGGKSE
SVANLQAQPS LNSIHSSPGP KRSTNTLKKW LTSPVRRLNS GKADGNIKKQ KKVRDGRKSF
DLGSPKPGDE TTPQGDSADE KSKKGWGEDE PDEESHTPLP PPMKIFDNDP TQDEMSSLLA
ARQASTEVPT AADLVNAIEK LVKNKLSLEG SSYRGSLKDP AGCLNEGMAP PTPPKNPEEE
QKAKALRGRM FVLNELVQTE KDYVKDLGIV VEGFMKRIEE KGVPEDMRGK DKIVFGNIHQ
IYDWHKDFFL AELEKCIQEQ DRLAQLFIKH ERKLHIYVWY CQNKPRSEYI VAEYDAYFEE
VKQEINQRLT LSDFLIKPIQ RITKYQLLLK DFLRYSEKAG LECSDIEKAV ELMCLVPKRC
NDMMNLGRLQ GFEGTLTAQG KLLQQDTFYV IELDAGMQSR TKERRVFLFE QIVIFSELLR
KGSLTPGYMF KRSIKMNYLV LEENVDNDPC KFALMNRETS ERVVLQAANA DIQQAWVQDI
NQVLETQRDF LNALQSPIEY QRKERSTAVM RSQPARLPQA SPRPYSSVPA GSEKPPKGSS
YNPPLPPLKI STSNGSPGFE YHQPGDKFEA SKQNDLGGCN GTSSMAVIKD YYALKENEIC
VSQGEVVQVL AVNQQNMCLV YQPASDHSPA AEGWVPGSIL APLTKATAAE SSDGSIKKSC
SWHTLRMRKR AEVENTGKNE ATGPRKPKDI LGNKVSVKET NSSEESECDD LDPNTSMEIL
NPNFIQEVAP EFLVPLVDVT CLLGDTVILQ CKVCGRPKPT ITWKGPDQNI LDTDNSSATY
TVSSCDSGEI TLKICNLMPQ DSGIYTCIAT NDHGTTSTSA TVKVQGVPAA PNRPIAQERS
CTSVILRWLP PSSTGNCTIS GYTVEYREEG SQIWQQSVAS TLDTYLVIED LSPGCPYQFR
VSASNPWGIS LPSEPSEFVR LPEYDAAADG ATISWKENFD SAYTELNEIG RGRFSIVKKC
IHKATRKDVA VKFVSKKMKK KEQAAHEAAL LQHLQHPQYI TLHDTYESPT SYILILELMD
DGRLLDYLMN HDELMEEKVA FYIRDIMEAL QYLHNCRVAH LDIKPENLLI DLRIPVPRVK
LIDLEDAVQI SGHFHIHHLL GNPEFAAPEV IQGIPVSLGT DIWSIGVLTY VMLSGVSPFL
DESKEETCIN VCRVDFSFPH EYFCGVSNAA RDFINVILQE DFRRRPTAAT CLQHPWLQPH
NGSYSKIPLD TSRLACFIER RKHQNDVRPI PNVKSYIVNR VNQGT
//
ID KALRN_HUMAN Reviewed; 2985 AA.
AC O60229; A8MSI4; C9JQ37; Q6ZN45; Q8TBQ5; Q9NSZ4; Q9Y2A5;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-OCT-2007, sequence version 2.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=Kalirin;
DE EC=2.7.11.1;
DE AltName: Full=Huntingtin-associated protein-interacting protein;
DE AltName: Full=Protein Duo;
DE AltName: Full=Serine/threonine-protein kinase with Dbl- and pleckstrin homology domain;
GN Name=KALRN; Synonyms=DUET, DUO, HAPIP, TRAD;
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] (ISOFORM 2).
RC TISSUE=Frontal cortex;
RX PubMed=9285789; DOI=10.1093/hmg/6.9.1519;
RA Colomer V., Engelender S., Sharp A.H., Duan K., Cooper J.K.,
RA Lanahan A., Lyford G., Worley P., Ross C.A.;
RT "Huntingtin-associated protein 1 (HAP1) binds to a Trio-like
RT polypeptide, with a rac1 guanine nucleotide exchange factor domain.";
RL Hum. Mol. Genet. 6:1519-1525(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), FUNCTION, MUTAGENESIS OF
RP LYS-2712, AUTOPHOSPHORYLATION, TISSUE SPECIFICITY, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Skeletal muscle;
RX PubMed=10023074; DOI=10.1016/S0378-1119(98)00605-2;
RA Kawai T., Sanjo H., Akira S.;
RT "Duet is a novel serine/threonine kinase with Dbl-homology (DH) and
RT pleckstrin-homology (PH) domains.";
RL Gene 227:249-255(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 5).
RC TISSUE=Amygdala, and Testis;
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=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1917 (ISOFORM 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2104-2985 (ISOFORM 5).
RC TISSUE=Kidney;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2016-2985 (ISOFORM 5).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP INVOLVEMENT IN CHDS5.
RX PubMed=17357071; DOI=10.1086/512981;
RA Wang L., Hauser E.R., Shah S.H., Pericak-Vance M.A., Haynes C.,
RA Crosslin D., Harris M. II, Nelson S., Hale A.B., Granger C.B.,
RA Haines J.L., Jones C.J.H., Crossman D., Seo D., Gregory S.G.,
RA Kraus W.E., Goldschmidt-Clermont P.J., Vance J.M.;
RT "Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a
RT novel candidate gene for coronary artery disease.";
RL Am. J. Hum. Genet. 80:650-663(2007).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1750; SER-1753;
RP SER-1799; SER-1817 AND SER-2261, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1799, AND MASS
RP 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 [11]
RP INTERACTION WITH FASLG.
RX PubMed=19807924; DOI=10.1186/1471-2172-10-53;
RA Voss M., Lettau M., Janssen O.;
RT "Identification of SH3 domain interaction partners of human FasL
RT (CD178) by phage display screening.";
RL BMC Immunol. 10:53-53(2009).
RN [12]
RP VARIANTS [LARGE SCALE ANALYSIS] TRP-213 AND CYS-1896.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [13]
RP VARIANT [LARGE SCALE ANALYSIS] LEU-196.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Promotes the exchange of GDP by GTP. Activates specific
CC Rho GTPase family members, thereby inducing various signaling
CC mechanisms that regulate neuronal shape, growth, and plasticity,
CC through their effects on the actin cytoskeleton. Induces
CC lamellipodia independent of its GEF activity.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- SUBUNIT: Interacts with the C-terminal of peptidylglycine alpha-
CC amidating monooxygenase (PAM) and with the huntingtin-associated
CC protein 1 (HAP1) (By similarity). Interacts with FASLG.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cytoskeleton.
CC Note=Associated with the cytoskeleton.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=6;
CC Name=1;
CC IsoId=O60229-1; Sequence=Displayed;
CC Note=Produced by alternative splicing;
CC Name=2;
CC IsoId=O60229-2; Sequence=VSP_028910, VSP_028911;
CC Note=Produced by alternative splicing. No experimental
CC confirmation available;
CC Name=3;
CC IsoId=O60229-3; Sequence=VSP_028905, VSP_028906, VSP_028907,
CC VSP_028908;
CC Note=Produced by alternative initiation at Met-624 of isoform 1.
CC Inferred by similarity;
CC Name=4; Synonyms=DUET, TRAD;
CC IsoId=O60229-4; Sequence=VSP_028903, VSP_028912, VSP_047353;
CC Note=Produced by alternative splicing;
CC Name=5;
CC IsoId=O60229-5; Sequence=VSP_028904, VSP_028909, VSP_028913,
CC VSP_028914, VSP_028915;
CC Note=Produced by alternative splicing;
CC Name=6;
CC IsoId=O60229-6; Sequence=VSP_028903, VSP_028912, VSP_028913;
CC Note=Produced by alternative splicing. No experimental
CC confirmation available;
CC -!- TISSUE SPECIFICITY: Isoform 2 is brain specific. Highly expressed
CC in cerebral cortex, putamen, amygdala, hippocampus and caudate
CC nucleus. Weakly expressed in brain stem and cerebellum. Isoform 4
CC is expressed in skeletal muscle.
CC -!- DOMAIN: The two GEF domains catalyze nucleotide exchange for RAC1
CC and RhoA which are bound by DH1 and DH2 respectively. The two GEF
CC domains appear to play differing roles in neuronal development and
CC axonal outgrowth. SH3 1 binds to the first GEF domain inhibiting
CC GEF activity only when in the presence of a PXXP peptide,
CC suggesting that the SH3 domain/peptide interaction mediates
CC binding to GEF1. CRK1 SH3 domain binds to and inhibits GEF1
CC activity (By similarity).
CC -!- PTM: Autophosphorylated.
CC -!- DISEASE: Coronary heart disease 5 (CHDS5) [MIM:608901]: A
CC multifactorial disease characterized by an imbalance between
CC myocardial functional requirements and the capacity of the
CC coronary vessels to supply sufficient blood flow. Decreased
CC capacity of the coronary vessels is often associated with
CC thickening and loss of elasticity of the coronary arteries.
CC Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Called DUO because the encoded protein is closely
CC related to but shorter than TRIO.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
CC Ser/Thr protein kinase family.
CC -!- SIMILARITY: Contains 1 CRAL-TRIO domain.
CC -!- SIMILARITY: Contains 2 DH (DBL-homology) domains.
CC -!- SIMILARITY: Contains 1 fibronectin type-III domain.
CC -!- SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like)
CC domain.
CC -!- SIMILARITY: Contains 2 PH domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 2 SH3 domains.
CC -!- SIMILARITY: Contains 5 spectrin repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH58015.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence;
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DR EMBL; U94190; AAC15791.1; -; mRNA.
DR EMBL; AB011422; BAA76314.1; -; mRNA.
DR EMBL; AK125979; BAC86373.1; -; mRNA.
DR EMBL; AK131379; BAD18530.1; -; mRNA.
DR EMBL; AC022336; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC069233; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC080008; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC112129; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC117401; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW79410.1; -; Genomic_DNA.
DR EMBL; BC026865; AAH26865.1; -; mRNA.
DR EMBL; BC058015; AAH58015.1; ALT_SEQ; mRNA.
DR EMBL; AL137629; CAB70850.1; -; mRNA.
DR PIR; T46482; T46482.
DR RefSeq; NP_001019831.2; NM_001024660.3.
DR RefSeq; NP_003938.1; NM_003947.4.
DR RefSeq; NP_008995.2; NM_007064.3.
DR UniGene; Hs.8004; -.
DR ProteinModelPortal; O60229; -.
DR SMR; O60229; 1279-1582, 1645-1711, 1918-2247, 2324-2389.
DR IntAct; O60229; 9.
DR MINT; MINT-2865643; -.
DR STRING; 9606.ENSP00000240874; -.
DR PhosphoSite; O60229; -.
DR PaxDb; O60229; -.
DR PRIDE; O60229; -.
DR DNASU; 8997; -.
DR Ensembl; ENST00000240874; ENSP00000240874; ENSG00000160145.
DR Ensembl; ENST00000291478; ENSP00000291478; ENSG00000160145.
DR Ensembl; ENST00000393496; ENSP00000377134; ENSG00000160145.
DR Ensembl; ENST00000428018; ENSP00000402419; ENSG00000160145.
DR GeneID; 8997; -.
DR KEGG; hsa:8997; -.
DR UCSC; uc003ehk.3; human.
DR CTD; 8997; -.
DR GeneCards; GC03P123798; -.
DR HGNC; HGNC:4814; KALRN.
DR HPA; CAB026456; -.
DR HPA; HPA011913; -.
DR MIM; 604605; gene.
DR MIM; 608901; phenotype.
DR neXtProt; NX_O60229; -.
DR PharmGKB; PA29189; -.
DR eggNOG; NOG331990; -.
DR HOGENOM; HOG000044462; -.
DR HOVERGEN; HBG108598; -.
DR InParanoid; O60229; -.
DR KO; K15048; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; O60229; -.
DR ChiTaRS; KALRN; human.
DR GeneWiki; Kalirin; -.
DR GenomeRNAi; 8997; -.
DR NextBio; 33739; -.
DR PRO; PR:O60229; -.
DR ArrayExpress; O60229; -.
DR Bgee; O60229; -.
DR CleanEx; HS_KALRN; -.
DR Genevestigator; O60229; -.
DR GO; GO:0015629; C:actin cytoskeleton; TAS:ProtInc.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:ProtInc.
DR GO; GO:0005089; F:Rho guanyl-nucleotide exchange factor activity; IEA:InterPro.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0007399; P:nervous system development; ISS:HGNC.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0016192; P:vesicle-mediated transport; TAS:ProtInc.
DR Gene3D; 1.20.900.10; -; 2.
DR Gene3D; 2.30.29.30; -; 2.
DR Gene3D; 2.60.40.10; -; 2.
DR Gene3D; 3.40.525.10; -; 1.
DR InterPro; IPR001251; CRAL-TRIO_dom.
DR InterPro; IPR000219; DH-domain.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR028569; Kalirin.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR001452; SH3_domain.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR InterPro; IPR002017; Spectrin_repeat.
DR PANTHER; PTHR22826:SF49; PTHR22826:SF49; 1.
DR Pfam; PF13716; CRAL_TRIO_2; 1.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF07679; I-set; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00621; RhoGEF; 2.
DR Pfam; PF00435; Spectrin; 4.
DR SMART; SM00060; FN3; 1.
DR SMART; SM00408; IGc2; 1.
DR SMART; SM00233; PH; 2.
DR SMART; SM00325; RhoGEF; 2.
DR SMART; SM00220; S_TKc; 1.
DR SMART; SM00516; SEC14; 1.
DR SMART; SM00326; SH3; 2.
DR SMART; SM00150; SPEC; 7.
DR SUPFAM; SSF48065; SSF48065; 2.
DR SUPFAM; SSF49265; SSF49265; 1.
DR SUPFAM; SSF50044; SSF50044; 2.
DR SUPFAM; SSF52087; SSF52087; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50191; CRAL_TRIO; 1.
DR PROSITE; PS00741; DH_1; FALSE_NEG.
DR PROSITE; PS50010; DH_2; 2.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
DR PROSITE; PS50003; PH_DOMAIN; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Cytoskeleton; Disulfide bond;
KW Guanine-nucleotide releasing factor; Immunoglobulin domain; Kinase;
KW Magnesium; Metal-binding; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; SH3 domain; Transferase.
FT CHAIN 1 2985 Kalirin.
FT /FTId=PRO_0000080955.
FT DOMAIN 35 180 CRAL-TRIO.
FT REPEAT 188 308 Spectrin 1.
FT REPEAT 310 416 Spectrin 2.
FT REPEAT 536 642 Spectrin 3.
FT REPEAT 890 1004 Spectrin 4.
FT REPEAT 1130 1222 Spectrin 5.
FT DOMAIN 1281 1456 DH 1.
FT DOMAIN 1468 1580 PH 1.
FT DOMAIN 1646 1711 SH3 1.
FT DOMAIN 1928 2103 DH 2.
FT DOMAIN 2115 2225 PH 2.
FT DOMAIN 2320 2385 SH3 2.
FT DOMAIN 2470 2563 Ig-like C2-type.
FT DOMAIN 2570 2664 Fibronectin type-III.
FT DOMAIN 2683 2937 Protein kinase.
FT NP_BIND 2689 2697 ATP (By similarity).
FT COMPBIAS 682 687 Poly-Gln.
FT ACT_SITE 2802 2802 Proton acceptor (By similarity).
FT BINDING 2712 2712 ATP.
FT MOD_RES 1750 1750 Phosphoserine.
FT MOD_RES 1753 1753 Phosphoserine.
FT MOD_RES 1799 1799 Phosphoserine.
FT MOD_RES 1817 1817 Phosphoserine.
FT MOD_RES 2261 2261 Phosphoserine.
FT DISULFID 2491 2547 By similarity.
FT VAR_SEQ 1 1697 Missing (in isoform 4 and isoform 6).
FT /FTId=VSP_028903.
FT VAR_SEQ 1 1627 Missing (in isoform 5).
FT /FTId=VSP_028904.
FT VAR_SEQ 1 641 Missing (in isoform 3).
FT /FTId=VSP_028905.
FT VAR_SEQ 709 721 Missing (in isoform 3).
FT /FTId=VSP_028906.
FT VAR_SEQ 1465 1505 FDENLDVQGELILQDAFQVWDPKSLIRKGRERHLFLFEISL
FT -> SCPPSTGEASSLPRHGGACIMGGKWHEVRQGARLEERR
FT NDK (in isoform 3).
FT /FTId=VSP_028907.
FT VAR_SEQ 1506 2985 Missing (in isoform 3).
FT /FTId=VSP_028908.
FT VAR_SEQ 1628 1643 ISIASRTSQNTVDSDK -> MLKWISWRQSKANKAQ (in
FT isoform 5).
FT /FTId=VSP_028909.
FT VAR_SEQ 1644 1663 LSGGCELTVVLQDFSAGHSS -> DGNLVPRWHLGPGDPFS
FT TYV (in isoform 2).
FT /FTId=VSP_028910.
FT VAR_SEQ 1664 2985 Missing (in isoform 2).
FT /FTId=VSP_028911.
FT VAR_SEQ 1698 1725 EGLVPSSALCISHSRSSVEMDCFFPLVK -> MKGGDRAYT
FT RGPSLGWLFAKCCCCFPCR (in isoform 4 and
FT isoform 6).
FT /FTId=VSP_028912.
FT VAR_SEQ 1857 1887 Missing (in isoform 5 and isoform 6).
FT /FTId=VSP_028913.
FT VAR_SEQ 1857 1857 S -> SS (in isoform 4).
FT /FTId=VSP_047353.
FT VAR_SEQ 2313 2313 Missing (in isoform 5).
FT /FTId=VSP_028914.
FT VAR_SEQ 2398 2985 Missing (in isoform 5).
FT /FTId=VSP_028915.
FT VARIANT 196 196 S -> L.
FT /FTId=VAR_041898.
FT VARIANT 213 213 R -> W (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035976.
FT VARIANT 1326 1326 E -> D (in dbSNP:rs2289838).
FT /FTId=VAR_020192.
FT VARIANT 1896 1896 S -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035625.
FT VARIANT 1929 1929 R -> M (in dbSNP:rs35298864).
FT /FTId=VAR_057190.
FT MUTAGEN 2712 2712 K->A: Loss of autophosphorylation.
FT CONFLICT 2458 2458 E -> G (in Ref. 2; BAA76314).
SQ SEQUENCE 2985 AA; 340174 MW; F4C01D0F2422A92F CRC64;
MTDRFWDQWY LWYLRLLRLL DRGSFRNDGL KASDVLPILK EKVAFVSGGR DKRGGPILTF
PARSNHDRIR QEDLRKLVTY LASVPSEDVC KRGFTVIIDM RGSKWDLIKP LLKTLQEAFP
AEIHVALIIK PDNFWQKQKT NFGSSKFIFE TSMVSVEGLT KLVDPSQLTE EFDGSLDYNH
EEWIELRLSL EEFFNSAVHL LSRLEDLQEM LARKEFPVDV EGSRRLIDEH TQLKKKVLKA
PVEELDREGQ RLLQCIRCSD GFSGRNCIPG SADFQSLVPK ITSLLDKLHS TRQHLHQMWH
VRKLKLDQCF QLRLFEQDAE KMFDWISHNK ELFLQSHTEI GVSYQYALDL QTQHNHFAMN
SMNAYVNINR IMSVASRLSE AGHYASQQIK QISTQLDQEW KSFAAALDER STILAMSAVF
HQKAEQFLSG VDAWCKMCSE GGLPSEMQDL ELAIHHHQTL YEQVTQAYTE VSQDGKALLD
VLQRPLSPGN SESLTATANY SKAVHQVLDV VHEVLHHQRR LESIWQHRKV RLHQRLQLCV
FQQDVQQVLD WIENHGEAFL SKHTGVGKSL HRARALQKRH DDFEEVAQNT YTNADKLLEA
AEQLAQTGEC DPEEIYKAAR HLEVRIQDFV RRVEQRKLLL DMSVSFHTHT KELWTWMEDL
QKEMLEDVCA DSVDAVQELI KQFQQQQTAT LDATLNVIKE GEDLIQQLRS APPSLGEPSE
ARDSAVSNNK TPHSSSISHI ESVLQQLDDA QVQMEELFHE RKIKLDIFLQ LRIFEQYTIE
VTAELDAWNE DLLRQMNDFN TEDLTLAEQR LQRHTERKLA MNNMTFEVIQ QGQDLHQYIT
EVQASGIELI CEKDIDLAAQ VQELLEFLHE KQHELELNAE QTHKRLEQCL QLRHLQAEVK
QVLGWIRNGE SMLNASLVNA SSLSEAEQLQ REHEQFQLAI ESLFHATSLQ KTHQSALQVQ
QKAEVLLQAG HYDADAIREC AEKVALHWQQ LMLKMEDRLK LVNASVAFYK TSEQVCSVLE
SLEQEYRRDE DWCGGRDKLG PAAEIDHVIP LISKHLEQKE AFLKACTLAR RNAEVFLKYI
HRNNVSMPSV ASHTRGPEQQ VKAILSELLQ RENRVLHFWT LKKRRLDQCQ QYVVFERSAK
QALDWIQETG EFYLSTHTST GETTEETQEL LKEYGEFRVP AKQTKEKVKL LIQLADSFVE
KGHIHATEIR KWVTTVDKHY RDFSLRMGKY RYSLEKALGV NTEDNKDLEL DIIPASLSDR
EVKLRDANHE VNEEKRKSAR KKEFIMAELL QTEKAYVRDL HECLETYLWE MTSGVEEIPP
GILNKEHIIF GNIQEIYDFH NNIFLKELEK YEQLPEDVGH CFVTWADKFQ MYVTYCKNKP
DSNQLILEHA GTFFDEIQQR HGLANSISSY LIKPVQRITK YQLLLKELLT CCEEGKGELK
DGLEVMLSVP KKANDAMHVS MLEGFDENLD VQGELILQDA FQVWDPKSLI RKGRERHLFL
FEISLVFSKE IKDSSGHTKY VYKNKLLTSE LGVTEHVEGD PCKFALWSGR TPSSDNKTVL
KASNIETKQE WIKNIREVIQ ERIIHLKGAL KEPLQLPKTP AKQRNNSKRD GVEDIDSQGD
GSSQPDTISI ASRTSQNTVD SDKLSGGCEL TVVLQDFSAG HSSELTIQVG QTVELLERPS
ERPGWCLVRT TERSPPLEGL VPSSALCISH SRSSVEMDCF FPLVKDAYSH SSSENGGKSE
SVANLQAQPS LNSIHSSPGP KRSTNTLKKW LTSPVRRLNS GKADGNIKKQ KKVRDGRKSF
DLGSPKPGDE TTPQGDSADE KSKKGWGEDE PDEESHTPLP PPMKIFDNDP TQDEMSSLLA
ARQASTEVPT AADLVNAIEK LVKNKLSLEG SSYRGSLKDP AGCLNEGMAP PTPPKNPEEE
QKAKALRGRM FVLNELVQTE KDYVKDLGIV VEGFMKRIEE KGVPEDMRGK DKIVFGNIHQ
IYDWHKDFFL AELEKCIQEQ DRLAQLFIKH ERKLHIYVWY CQNKPRSEYI VAEYDAYFEE
VKQEINQRLT LSDFLIKPIQ RITKYQLLLK DFLRYSEKAG LECSDIEKAV ELMCLVPKRC
NDMMNLGRLQ GFEGTLTAQG KLLQQDTFYV IELDAGMQSR TKERRVFLFE QIVIFSELLR
KGSLTPGYMF KRSIKMNYLV LEENVDNDPC KFALMNRETS ERVVLQAANA DIQQAWVQDI
NQVLETQRDF LNALQSPIEY QRKERSTAVM RSQPARLPQA SPRPYSSVPA GSEKPPKGSS
YNPPLPPLKI STSNGSPGFE YHQPGDKFEA SKQNDLGGCN GTSSMAVIKD YYALKENEIC
VSQGEVVQVL AVNQQNMCLV YQPASDHSPA AEGWVPGSIL APLTKATAAE SSDGSIKKSC
SWHTLRMRKR AEVENTGKNE ATGPRKPKDI LGNKVSVKET NSSEESECDD LDPNTSMEIL
NPNFIQEVAP EFLVPLVDVT CLLGDTVILQ CKVCGRPKPT ITWKGPDQNI LDTDNSSATY
TVSSCDSGEI TLKICNLMPQ DSGIYTCIAT NDHGTTSTSA TVKVQGVPAA PNRPIAQERS
CTSVILRWLP PSSTGNCTIS GYTVEYREEG SQIWQQSVAS TLDTYLVIED LSPGCPYQFR
VSASNPWGIS LPSEPSEFVR LPEYDAAADG ATISWKENFD SAYTELNEIG RGRFSIVKKC
IHKATRKDVA VKFVSKKMKK KEQAAHEAAL LQHLQHPQYI TLHDTYESPT SYILILELMD
DGRLLDYLMN HDELMEEKVA FYIRDIMEAL QYLHNCRVAH LDIKPENLLI DLRIPVPRVK
LIDLEDAVQI SGHFHIHHLL GNPEFAAPEV IQGIPVSLGT DIWSIGVLTY VMLSGVSPFL
DESKEETCIN VCRVDFSFPH EYFCGVSNAA RDFINVILQE DFRRRPTAAT CLQHPWLQPH
NGSYSKIPLD TSRLACFIER RKHQNDVRPI PNVKSYIVNR VNQGT
//
MIM
604605
*RECORD*
*FIELD* NO
604605
*FIELD* TI
*604605 KALIRIN; KALRN
HUNTINGTIN-ASSOCIATED PROTEIN-INTERACTING PROTEIN, INCLUDED; HAPIP,
read moreINCLUDED;;
DUO, INCLUDED;;
SERINE/THREONINE PROTEIN KINASE WITH DBL HOMOLOGY AND PLECKSTRIN HOMOLOGY
DOMAINS, INCLUDED; DUET, INCLUDED
*FIELD* TX
DESCRIPTION
Kalirin is a multidomain guanine nucleotide exchange factor (GEF) for
small GTP-binding proteins of the Rho family (see 165390). Multiple
kalirin isoforms containing different combinations of functional domains
are expressed, and kalirin shows a complex expression pattern during
brain development (McPherson et al., 2004).
CLONING
Using a yeast 2-hybrid screen with HAP1 (600947) as bait, Colomer et al.
(1997) identified a human brain cDNA for HAPIP, or huntingtin
(613004)-associated protein-interacting protein, which they called DUO
because the encoded protein is closely related to but shorter than TRIO
(601893). The deduced HAPIP protein contains 1,663 amino acids and is
80.6% identical to human TRIO and 98.5% identical to rat Duo (PCIP10),
which was found by Alam et al. (1996) to interact with peptidylglycine
alpha-amidating monooxygenase (PAM; 170270). DUO contains a GEF domain,
a pleckstrin (PLEK; 173570) homology (PH) domain, and 4 or 5 spectrin
(see 182790)-like repeat units. Northern blot analysis revealed 2
brain-specific mRNAs of approximately 7.0 kb and 4.7 kb expressed at
high levels in cerebral cortex, putamen, amygdala, hippocampus, and
caudate nucleus and at lower levels in brainstem and cerebellum. Some of
these regions are affected in Huntington disease (143100).
By screening a rat hippocampus cDNA library with a partial Pcip10 cDNA
and using 3-prime RACE, Alam et al. (1997) isolated a full-length Pcip10
cDNA, which they termed kalirin because of its ability to interact with
multiple proteins and its spectrin-like domains (Kali, the Hindu goddess
with many hands). Kalirin encodes a deduced 1,899-amino acid, acidic (pI
5.67) cytosolic protein.
By searching for ESTs sharing similarity with the catalytic domain of
DAP kinase (DAPK; 600831), followed by screening a skeletal muscle cDNA
library, Kawai et al. (1999) cloned DUET, an isoform of kalirin (Johnson
et al., 2000). Northern blot analysis detected expression of DUET in
skeletal muscle, with little to no expression in other tissues.
Epitope-tagged DUET associated with cytoskeletal elements and was found
in the insoluble fraction of transfected mouse fibroblasts.
McPherson et al. (2002) stated that the full-length rat kalirin isoform,
kalirin-12, contains an N-terminal Sec14 (see 601504)-like lipid-binding
motif, 9 spectrin-like repeats, 2 Dbl (MCF2; 311030) homology (DH)/PH
GEF domains, 2 SRC (190090) homology-3 (SH3) domains, 1 Ig-like domain,
1 fibronectin-1 (FN1; 135600)-like (FN3) domain, and a C-terminal
serine/threonine protein kinase domain. Human HAPIP/Duo corresponds to
rat kalirin-7, which is truncated following the first DH/PH GEF domain
of kalirin-12. The human Duet transcript begins with a short alternative
exon within intron 34 and encodes a protein with a unique 28-amino acid
N terminus, followed by the second DH/PH GEF domain and C-terminal
kinase domain of kalirin-12. Two other rat isoforms, kalirin-8 and -9,
are truncated following the first and second SH3 domains of kalirin-12,
respectively. By PCR of a human brain cDNA library, McPherson et al.
(2002) cloned human kalirin-12 and kalirin-9; kalirin-8 was not
expressed in human. McPherson et al. (2002) also cloned several novel
kalirin variants in rat and human, including a Duet variant containing
the unique 3-prime end of kalirin-9 and the delta-kalirins, which are
initiated within intron 10 and encode proteins that lack the N-terminal
Sec14-like motif and the first 4 spectrin repeats of kalirin-12. The
delta-kalirins can terminate with the unique 3-prime ends of kalirin-7,
-8, -9, or -12. RT-PCR of human tissues showed that kalirin-7, -9, and
-12 and the delta-kalirins were predominantly expressed in brain.
Kalirin-7 showed higher expression in adult brain, whereas kalirin-9 and
-12 showed higher expression in fetal brain. Except for kalirin-7, all
of these variants were expressed at lower levels or were undetectable in
spinal cord and fetal liver. In contrast, the Duet variants were
expressed at higher levels in spinal cord and fetal liver than in fetal
and adult brain.
By EST database analysis, McPherson et al. (2004) identified human
kalirin transcripts containing alternative first exons. Exons 1B, 1C,
and 1E encode unique N-terminal sequences of 23 to 25 amino acids. Exon
1F contains a stop codon in frame with exon 2, resulting in a truncated
protein that is translated from a start codon in exon 4. RT-PCR of human
tissues detected expression of exons 1B, 1C, and 1F, as well as the
delta 5-prime end, in adult and fetal brain. Exons 1B and 1C were also
expressed in spinal cord, and exon 1B was expressed in fetal liver. Exon
1B was the predominant 5-prime end, and expression of exon 1E was not
detected. The SH-SY5Y human neuroblastoma cell line expressed all
kalirin first exons except 1E. Sequences corresponding to human exons 1E
and 1F were not present in mouse and rat genomes.
GENE FUNCTION
By Western blot and immunoprecipitation analyses, Alam et al. (1997)
found that kalirin bound to RAC1 (602048), which is involved in
regulating actin organization, endocytosis, exocytosis, and free radical
production. Kalirin expressed in corticotrope tumor cells also enhanced
turnover of newly synthesized PAM. Cells stably expressing both kalirin
and PAM produced longer and more highly branched neuritic processes than
nontransfected cells or cell expressing only PAM.
By in vitro kinase assay of DUET expressed by transfected COS-7 cells,
Kawai et al. (1999) demonstrated autophosphorylation. Substitution of a
conserved lysine with alanine in kinase subdomain II of DUET, which
blocks ATP binding, resulted in expression of an inactive protein.
Unlike DAPK, DUET was unable to phosphorylate myosin light chain (see
160781).
McPherson et al. (2004) found that expression of kalirin-7 and -9, the
delta-kalirins, and kalirins containing exon 1C in SH-SY5Y cells varied
depending on the type of culture media used. Retinoic acid treatment,
which induces neuronal differentiation in SH-SY5Y cells, increased
expression of the delta-kalirins and decreased expression of kalirins
with exon 1C. Expression of other kalirin transcripts was not affected
by culture media or retinoic acid treatment.
Ferraro et al. (2007) showed that some isoforms of kalirin and Trio
colocalized with immature secretory granules in mouse and rat
neuroendocrine cells and modulated their cargo secretion. Overexpression
of their N-terminal GEF domains enhanced secretion from immature
granules, depleting cells of secretory cargo in the absence of
secretagogue. This response required GEF activity and was mimicked by
kalirin/Trio substrates Rac1 (602048) and RhoG (179505). Selective
pharmacologic inhibition of endogenous GEF activity decreased
secretagogue-independent release of hormone precursors, causing
accumulation of product peptide in mature secretory granules. Ferraro et
al. (2007) concluded that kalirin/TRIO modulation of cargo secretion
from immature granules provides secretory cells with an extra layer of
control over the sets of peptides released and enhances the range of
physiologic responses that can be elicited.
Ma et al. (2008) stated that kalirin-7, which contains a C-terminal
PDZ-binding motif, is the most prevalent kalirin isoform in adult rat
hippocampus. They showed that kalirin-7 localized to the postsynaptic
density, interacted with Psd95 (DLG4; 602887), and caused formation of
dendritic spines when overexpressed in rat pyramidal neurons. In
hippocampal aspiny interneurons, where the level of kalirin-7 was low,
kalirin-7 localized to the postsynaptic side of excitatory synapses on
dendritic shafts and colocalized with clusters of Psd95 and NMDA
receptor subunit Nr1 (GRIN1; 138249). Selectively decreasing levels of
kalirin-7 decreased the density of Psd95-positive, bassoon (BSN;
604020)-positive clusters along the dendritic shaft of hippocampal
interneurons. Overexpression of kalirin-7 increased dendritic branching
and induced formation of spine-like structures along the dendrites and
on the soma of normally aspiny hippocampal interneurons. Essentially all
of the spine-like structures formed in response to kalirin-7 were
apposed to vesicular glutamate transporter-1 (SLC17A7; 605208)-positive,
bassoon-positive presynaptic endings, with GAD (see 605363)-positive,
vesicular GABA transporter (SLC32A1)-positive inhibitory endings being
unaffected. Almost every kalirin-7-positive dendritic cluster contained
Psd95 along with Nr1 and the AMPA receptor subunits Glur1 (GRIA1;
138248) and Glur2 (GRIA2; 138247). Kalirin-7-induced formation of
spine-like structures required its PDZ-binding motif, and interruption
of interactions between the PDZ-binding motif and its interactors
decreased kalirin-7-induced formation of spine-like structures.
GENE STRUCTURE
McPherson et al. (2002) determined that the KALRN gene contains 60
coding exons and spans more than 600 kb. Intron 10 contains an internal
start site from which the delta-kalirin transcripts initiate.
McPherson et al. (2004) identified 4 alternative first exons of the
KALRN gene, arranged in the order 5-prime-1B-1E-1C-1F-3-prime. Exons 1B,
1E, and 1C contain promoter regions and short coding sequences. Exon 1F
lies immediately upstream and contiguous with exon 2 and contains a
promoter region, but no coding sequence. Because exon 1F contains a stop
codon, transcripts containing exon 1F are translated from a start codon
in exon 4. None of the promoters contain canonical TATA boxes, but exons
1B and 1C contain AT-rich sequences that may function as TATA boxes. All
promoters have a unique complement of transcription factor-binding
sites.
MAPPING
Wang et al. (2007) identified the KALRN gene at chromosome 3q13 in a
fine-mapping study of the chromosome 3q region linked to early-onset
coronary artery disease (CHDS5; 608901).
MOLECULAR GENETICS
Following up on a susceptibility locus for coronary artery disease (CAD)
that had been mapped to 3q13-q21 in a linkage study of early-onset CAD
(CHDS5; 608901), Wang et al. (2007) completed an association-mapping
study across the 1-lod-unit-down supporting interval, to evaluate
association under the peak. The peakwide survey found evidence of
association of single-nucleotide polymorphisms (SNPs) from multiple
genes. The strongest associations were found in 3 SNPs from the KALRN
gene, especially in patients with early-onset CAD. Investigation of the
KALRN gene found that an intronic SNP (604605.0001) was associated with
early-onset CAD in all white data sets examined (P less than 0.05). In
the joint analysis of 332 white, early-onset CAD cases and 546 controls,
this SNP was highly significant (P = 0.00008), with an odds ratio
estimate of 2.1. Furthermore, the risk allele of this SNP was associated
with atherosclerosis burden (P = 0.03) in 145 human aortas. The highly
associated SNP resided in the first intron of an alternative transcript
of the KALRN gene. KALRN is a protein with many functions, including the
inhibition of inducible nitric oxide synthase (INOS; 163730) and guanine
exchange factor activity. KALRN and 2 other associated genes identified
in this study, CDGAP and MYLK (600922), participate in the Rho GTPase
signaling pathway. Wang et al. (2007) concluded that the data suggested
the importance of the KALRN gene and the Rho GTPase signaling pathway in
the pathogenesis of CAD.
*FIELD* AV
.0001
CORONARY HEART DISEASE, SUSCEPTIBILITY TO, 5
KALRN, G-T
In a peakwide association mapping study of the chromosome 3q13 region
associated with early-onset coronary artery disease (CHDS5; 608901),
Wang et al. (2007) found significant association of a single-nucleotide
polymorphism (SNP) in the first intron of an alternative transcript of
the KALRN gene, dbSNP rs9289231, with early-onset coronary artery
disease in all white data sets examined (p = 0.05). In the joint
analysis of 332 white, early-onset coronary artery disease cases and 546
controls, this SNP was highly significant (P = 0.00008), with an odds
ratio estimate of 2.1. Furthermore, the risk allele of this SNP was
associated with atherosclerosis burden (P = 0.03) in 145 human aortas.
*FIELD* RF
1. Alam, M. R.; Caldwell, B. D.; Johnson, R. C.; Darlington, D. N.;
Mains, R. E.; Eipper, B. A.: Novel proteins that interact with the
COOH-terminal cytosolic routing determinants of an integral membrane
peptide-processing enzyme. J. Biol. Chem. 271: 28636-28640, 1996.
2. Alam, M. R.; Johnson, R. C.; Darlington, D. N.; Hand, T. A.; Mains,
R. E.; Eipper, B. A.: Kalirin, a cytosolic protein with spectrin-like
and GDP/GTP exchange factor-like domains that interacts with peptidylglycine
alpha-amidating monooxygenase, an integral membrane peptide-processing
enzyme. J. Biol. Chem. 272: 12667-12675, 1997.
3. Colomer, V.; Engelender, S.; Sharp, A. H.; Duan, K.; Cooper, J.
K.; Lanahan, A.; Lyford, G.; Worley, P.; Ross, C. A.: Huntingtin-associated
protein 1 (HAP1) binds to a Trio-like polypeptide, with a rac1 guanine
nucleotide exchange factor domain. Hum. Molec. Genet. 6: 1519-1525,
1997.
4. Ferraro, F.; Ma, X.-M.; Sobota, J. A.; Eipper, B. A.; Mains, R.
E.: Kalirin/Trio Rho guanine nucleotide exchange factors regulate
a novel step in secretory granule maturation. Molec. Biol. Cell 18:
4813-4825, 2007.
5. Johnson, R. C.; Penzes, P.; Eipper, B. A.; Mains, R. E.: Isoforms
of kalirin, a neuronal Dbl family member, generated through use of
different 5-prime- and 3-prime-ends along with an internal translational
initiation site. J. Biol. Chem. 275: 19324-19333, 2000.
6. Kawai, T.; Sanjo, H.; Akira, S.: Duet is a novel serine/threonine
kinase with Dbl-homology (DH) and pleckstrin-homology (PH) domains. Gene 227:
249-255, 1999.
7. Ma, X.-M.; Wang, Y.; Ferraro, F.; Mains, R. E.; Eipper, B. A.:
Kalirin-7 is an essential component of both shaft and spine excitatory
synapses in hippocampal interneurons. J. Neurosci. 28: 711-724,
2008.
8. McPherson, C. E.; Eipper, B. A.; Mains, R. E.: Genomic organization
and differential expression of Kalirin isoforms. Gene 284: 41-51,
2002.
9. McPherson, C. E.; Eipper, B. A.; Mains, R. E.: Kalirin expression
is regulated by multiple promoters. J. Molec. Neurosci. 22: 51-62,
2004.
10. Wang, L.; Hauser, E. R.; Shah, S. H.; Pericak-Vance, M. A.; Haynes,
C.; Crosslin, D.; Harris, M., II; Nelson, S.; Hale, A. B.; Granger,
C. B.; Haines, J. L.; Jones, C. J. H.; Crossman, D.; Seo, D.; Gregory,
S. G.; Kraus, W. E.; Goldschmidt-Clermont, P. J.; Vance, J. M.: Peakwide
mapping on chromosome 3q13 identifies the kalirin gene as a novel
candidate gene for coronary artery disease. Am. J. Hum. Genet. 80:
650-663, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 3/21/2008
Victor A. McKusick - updated: 3/23/2007
*FIELD* CD
Paul J. Converse: 2/24/2000
*FIELD* ED
alopez: 11/20/2013
wwang: 9/15/2009
mgross: 3/26/2008
terry: 3/21/2008
alopez: 2/14/2008
alopez: 6/26/2007
alopez: 3/27/2007
terry: 3/23/2007
carol: 10/10/2006
terry: 3/3/2005
alopez: 10/29/2003
terry: 10/29/2003
carol: 2/28/2000
*RECORD*
*FIELD* NO
604605
*FIELD* TI
*604605 KALIRIN; KALRN
HUNTINGTIN-ASSOCIATED PROTEIN-INTERACTING PROTEIN, INCLUDED; HAPIP,
read moreINCLUDED;;
DUO, INCLUDED;;
SERINE/THREONINE PROTEIN KINASE WITH DBL HOMOLOGY AND PLECKSTRIN HOMOLOGY
DOMAINS, INCLUDED; DUET, INCLUDED
*FIELD* TX
DESCRIPTION
Kalirin is a multidomain guanine nucleotide exchange factor (GEF) for
small GTP-binding proteins of the Rho family (see 165390). Multiple
kalirin isoforms containing different combinations of functional domains
are expressed, and kalirin shows a complex expression pattern during
brain development (McPherson et al., 2004).
CLONING
Using a yeast 2-hybrid screen with HAP1 (600947) as bait, Colomer et al.
(1997) identified a human brain cDNA for HAPIP, or huntingtin
(613004)-associated protein-interacting protein, which they called DUO
because the encoded protein is closely related to but shorter than TRIO
(601893). The deduced HAPIP protein contains 1,663 amino acids and is
80.6% identical to human TRIO and 98.5% identical to rat Duo (PCIP10),
which was found by Alam et al. (1996) to interact with peptidylglycine
alpha-amidating monooxygenase (PAM; 170270). DUO contains a GEF domain,
a pleckstrin (PLEK; 173570) homology (PH) domain, and 4 or 5 spectrin
(see 182790)-like repeat units. Northern blot analysis revealed 2
brain-specific mRNAs of approximately 7.0 kb and 4.7 kb expressed at
high levels in cerebral cortex, putamen, amygdala, hippocampus, and
caudate nucleus and at lower levels in brainstem and cerebellum. Some of
these regions are affected in Huntington disease (143100).
By screening a rat hippocampus cDNA library with a partial Pcip10 cDNA
and using 3-prime RACE, Alam et al. (1997) isolated a full-length Pcip10
cDNA, which they termed kalirin because of its ability to interact with
multiple proteins and its spectrin-like domains (Kali, the Hindu goddess
with many hands). Kalirin encodes a deduced 1,899-amino acid, acidic (pI
5.67) cytosolic protein.
By searching for ESTs sharing similarity with the catalytic domain of
DAP kinase (DAPK; 600831), followed by screening a skeletal muscle cDNA
library, Kawai et al. (1999) cloned DUET, an isoform of kalirin (Johnson
et al., 2000). Northern blot analysis detected expression of DUET in
skeletal muscle, with little to no expression in other tissues.
Epitope-tagged DUET associated with cytoskeletal elements and was found
in the insoluble fraction of transfected mouse fibroblasts.
McPherson et al. (2002) stated that the full-length rat kalirin isoform,
kalirin-12, contains an N-terminal Sec14 (see 601504)-like lipid-binding
motif, 9 spectrin-like repeats, 2 Dbl (MCF2; 311030) homology (DH)/PH
GEF domains, 2 SRC (190090) homology-3 (SH3) domains, 1 Ig-like domain,
1 fibronectin-1 (FN1; 135600)-like (FN3) domain, and a C-terminal
serine/threonine protein kinase domain. Human HAPIP/Duo corresponds to
rat kalirin-7, which is truncated following the first DH/PH GEF domain
of kalirin-12. The human Duet transcript begins with a short alternative
exon within intron 34 and encodes a protein with a unique 28-amino acid
N terminus, followed by the second DH/PH GEF domain and C-terminal
kinase domain of kalirin-12. Two other rat isoforms, kalirin-8 and -9,
are truncated following the first and second SH3 domains of kalirin-12,
respectively. By PCR of a human brain cDNA library, McPherson et al.
(2002) cloned human kalirin-12 and kalirin-9; kalirin-8 was not
expressed in human. McPherson et al. (2002) also cloned several novel
kalirin variants in rat and human, including a Duet variant containing
the unique 3-prime end of kalirin-9 and the delta-kalirins, which are
initiated within intron 10 and encode proteins that lack the N-terminal
Sec14-like motif and the first 4 spectrin repeats of kalirin-12. The
delta-kalirins can terminate with the unique 3-prime ends of kalirin-7,
-8, -9, or -12. RT-PCR of human tissues showed that kalirin-7, -9, and
-12 and the delta-kalirins were predominantly expressed in brain.
Kalirin-7 showed higher expression in adult brain, whereas kalirin-9 and
-12 showed higher expression in fetal brain. Except for kalirin-7, all
of these variants were expressed at lower levels or were undetectable in
spinal cord and fetal liver. In contrast, the Duet variants were
expressed at higher levels in spinal cord and fetal liver than in fetal
and adult brain.
By EST database analysis, McPherson et al. (2004) identified human
kalirin transcripts containing alternative first exons. Exons 1B, 1C,
and 1E encode unique N-terminal sequences of 23 to 25 amino acids. Exon
1F contains a stop codon in frame with exon 2, resulting in a truncated
protein that is translated from a start codon in exon 4. RT-PCR of human
tissues detected expression of exons 1B, 1C, and 1F, as well as the
delta 5-prime end, in adult and fetal brain. Exons 1B and 1C were also
expressed in spinal cord, and exon 1B was expressed in fetal liver. Exon
1B was the predominant 5-prime end, and expression of exon 1E was not
detected. The SH-SY5Y human neuroblastoma cell line expressed all
kalirin first exons except 1E. Sequences corresponding to human exons 1E
and 1F were not present in mouse and rat genomes.
GENE FUNCTION
By Western blot and immunoprecipitation analyses, Alam et al. (1997)
found that kalirin bound to RAC1 (602048), which is involved in
regulating actin organization, endocytosis, exocytosis, and free radical
production. Kalirin expressed in corticotrope tumor cells also enhanced
turnover of newly synthesized PAM. Cells stably expressing both kalirin
and PAM produced longer and more highly branched neuritic processes than
nontransfected cells or cell expressing only PAM.
By in vitro kinase assay of DUET expressed by transfected COS-7 cells,
Kawai et al. (1999) demonstrated autophosphorylation. Substitution of a
conserved lysine with alanine in kinase subdomain II of DUET, which
blocks ATP binding, resulted in expression of an inactive protein.
Unlike DAPK, DUET was unable to phosphorylate myosin light chain (see
160781).
McPherson et al. (2004) found that expression of kalirin-7 and -9, the
delta-kalirins, and kalirins containing exon 1C in SH-SY5Y cells varied
depending on the type of culture media used. Retinoic acid treatment,
which induces neuronal differentiation in SH-SY5Y cells, increased
expression of the delta-kalirins and decreased expression of kalirins
with exon 1C. Expression of other kalirin transcripts was not affected
by culture media or retinoic acid treatment.
Ferraro et al. (2007) showed that some isoforms of kalirin and Trio
colocalized with immature secretory granules in mouse and rat
neuroendocrine cells and modulated their cargo secretion. Overexpression
of their N-terminal GEF domains enhanced secretion from immature
granules, depleting cells of secretory cargo in the absence of
secretagogue. This response required GEF activity and was mimicked by
kalirin/Trio substrates Rac1 (602048) and RhoG (179505). Selective
pharmacologic inhibition of endogenous GEF activity decreased
secretagogue-independent release of hormone precursors, causing
accumulation of product peptide in mature secretory granules. Ferraro et
al. (2007) concluded that kalirin/TRIO modulation of cargo secretion
from immature granules provides secretory cells with an extra layer of
control over the sets of peptides released and enhances the range of
physiologic responses that can be elicited.
Ma et al. (2008) stated that kalirin-7, which contains a C-terminal
PDZ-binding motif, is the most prevalent kalirin isoform in adult rat
hippocampus. They showed that kalirin-7 localized to the postsynaptic
density, interacted with Psd95 (DLG4; 602887), and caused formation of
dendritic spines when overexpressed in rat pyramidal neurons. In
hippocampal aspiny interneurons, where the level of kalirin-7 was low,
kalirin-7 localized to the postsynaptic side of excitatory synapses on
dendritic shafts and colocalized with clusters of Psd95 and NMDA
receptor subunit Nr1 (GRIN1; 138249). Selectively decreasing levels of
kalirin-7 decreased the density of Psd95-positive, bassoon (BSN;
604020)-positive clusters along the dendritic shaft of hippocampal
interneurons. Overexpression of kalirin-7 increased dendritic branching
and induced formation of spine-like structures along the dendrites and
on the soma of normally aspiny hippocampal interneurons. Essentially all
of the spine-like structures formed in response to kalirin-7 were
apposed to vesicular glutamate transporter-1 (SLC17A7; 605208)-positive,
bassoon-positive presynaptic endings, with GAD (see 605363)-positive,
vesicular GABA transporter (SLC32A1)-positive inhibitory endings being
unaffected. Almost every kalirin-7-positive dendritic cluster contained
Psd95 along with Nr1 and the AMPA receptor subunits Glur1 (GRIA1;
138248) and Glur2 (GRIA2; 138247). Kalirin-7-induced formation of
spine-like structures required its PDZ-binding motif, and interruption
of interactions between the PDZ-binding motif and its interactors
decreased kalirin-7-induced formation of spine-like structures.
GENE STRUCTURE
McPherson et al. (2002) determined that the KALRN gene contains 60
coding exons and spans more than 600 kb. Intron 10 contains an internal
start site from which the delta-kalirin transcripts initiate.
McPherson et al. (2004) identified 4 alternative first exons of the
KALRN gene, arranged in the order 5-prime-1B-1E-1C-1F-3-prime. Exons 1B,
1E, and 1C contain promoter regions and short coding sequences. Exon 1F
lies immediately upstream and contiguous with exon 2 and contains a
promoter region, but no coding sequence. Because exon 1F contains a stop
codon, transcripts containing exon 1F are translated from a start codon
in exon 4. None of the promoters contain canonical TATA boxes, but exons
1B and 1C contain AT-rich sequences that may function as TATA boxes. All
promoters have a unique complement of transcription factor-binding
sites.
MAPPING
Wang et al. (2007) identified the KALRN gene at chromosome 3q13 in a
fine-mapping study of the chromosome 3q region linked to early-onset
coronary artery disease (CHDS5; 608901).
MOLECULAR GENETICS
Following up on a susceptibility locus for coronary artery disease (CAD)
that had been mapped to 3q13-q21 in a linkage study of early-onset CAD
(CHDS5; 608901), Wang et al. (2007) completed an association-mapping
study across the 1-lod-unit-down supporting interval, to evaluate
association under the peak. The peakwide survey found evidence of
association of single-nucleotide polymorphisms (SNPs) from multiple
genes. The strongest associations were found in 3 SNPs from the KALRN
gene, especially in patients with early-onset CAD. Investigation of the
KALRN gene found that an intronic SNP (604605.0001) was associated with
early-onset CAD in all white data sets examined (P less than 0.05). In
the joint analysis of 332 white, early-onset CAD cases and 546 controls,
this SNP was highly significant (P = 0.00008), with an odds ratio
estimate of 2.1. Furthermore, the risk allele of this SNP was associated
with atherosclerosis burden (P = 0.03) in 145 human aortas. The highly
associated SNP resided in the first intron of an alternative transcript
of the KALRN gene. KALRN is a protein with many functions, including the
inhibition of inducible nitric oxide synthase (INOS; 163730) and guanine
exchange factor activity. KALRN and 2 other associated genes identified
in this study, CDGAP and MYLK (600922), participate in the Rho GTPase
signaling pathway. Wang et al. (2007) concluded that the data suggested
the importance of the KALRN gene and the Rho GTPase signaling pathway in
the pathogenesis of CAD.
*FIELD* AV
.0001
CORONARY HEART DISEASE, SUSCEPTIBILITY TO, 5
KALRN, G-T
In a peakwide association mapping study of the chromosome 3q13 region
associated with early-onset coronary artery disease (CHDS5; 608901),
Wang et al. (2007) found significant association of a single-nucleotide
polymorphism (SNP) in the first intron of an alternative transcript of
the KALRN gene, dbSNP rs9289231, with early-onset coronary artery
disease in all white data sets examined (p = 0.05). In the joint
analysis of 332 white, early-onset coronary artery disease cases and 546
controls, this SNP was highly significant (P = 0.00008), with an odds
ratio estimate of 2.1. Furthermore, the risk allele of this SNP was
associated with atherosclerosis burden (P = 0.03) in 145 human aortas.
*FIELD* RF
1. Alam, M. R.; Caldwell, B. D.; Johnson, R. C.; Darlington, D. N.;
Mains, R. E.; Eipper, B. A.: Novel proteins that interact with the
COOH-terminal cytosolic routing determinants of an integral membrane
peptide-processing enzyme. J. Biol. Chem. 271: 28636-28640, 1996.
2. Alam, M. R.; Johnson, R. C.; Darlington, D. N.; Hand, T. A.; Mains,
R. E.; Eipper, B. A.: Kalirin, a cytosolic protein with spectrin-like
and GDP/GTP exchange factor-like domains that interacts with peptidylglycine
alpha-amidating monooxygenase, an integral membrane peptide-processing
enzyme. J. Biol. Chem. 272: 12667-12675, 1997.
3. Colomer, V.; Engelender, S.; Sharp, A. H.; Duan, K.; Cooper, J.
K.; Lanahan, A.; Lyford, G.; Worley, P.; Ross, C. A.: Huntingtin-associated
protein 1 (HAP1) binds to a Trio-like polypeptide, with a rac1 guanine
nucleotide exchange factor domain. Hum. Molec. Genet. 6: 1519-1525,
1997.
4. Ferraro, F.; Ma, X.-M.; Sobota, J. A.; Eipper, B. A.; Mains, R.
E.: Kalirin/Trio Rho guanine nucleotide exchange factors regulate
a novel step in secretory granule maturation. Molec. Biol. Cell 18:
4813-4825, 2007.
5. Johnson, R. C.; Penzes, P.; Eipper, B. A.; Mains, R. E.: Isoforms
of kalirin, a neuronal Dbl family member, generated through use of
different 5-prime- and 3-prime-ends along with an internal translational
initiation site. J. Biol. Chem. 275: 19324-19333, 2000.
6. Kawai, T.; Sanjo, H.; Akira, S.: Duet is a novel serine/threonine
kinase with Dbl-homology (DH) and pleckstrin-homology (PH) domains. Gene 227:
249-255, 1999.
7. Ma, X.-M.; Wang, Y.; Ferraro, F.; Mains, R. E.; Eipper, B. A.:
Kalirin-7 is an essential component of both shaft and spine excitatory
synapses in hippocampal interneurons. J. Neurosci. 28: 711-724,
2008.
8. McPherson, C. E.; Eipper, B. A.; Mains, R. E.: Genomic organization
and differential expression of Kalirin isoforms. Gene 284: 41-51,
2002.
9. McPherson, C. E.; Eipper, B. A.; Mains, R. E.: Kalirin expression
is regulated by multiple promoters. J. Molec. Neurosci. 22: 51-62,
2004.
10. Wang, L.; Hauser, E. R.; Shah, S. H.; Pericak-Vance, M. A.; Haynes,
C.; Crosslin, D.; Harris, M., II; Nelson, S.; Hale, A. B.; Granger,
C. B.; Haines, J. L.; Jones, C. J. H.; Crossman, D.; Seo, D.; Gregory,
S. G.; Kraus, W. E.; Goldschmidt-Clermont, P. J.; Vance, J. M.: Peakwide
mapping on chromosome 3q13 identifies the kalirin gene as a novel
candidate gene for coronary artery disease. Am. J. Hum. Genet. 80:
650-663, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 3/21/2008
Victor A. McKusick - updated: 3/23/2007
*FIELD* CD
Paul J. Converse: 2/24/2000
*FIELD* ED
alopez: 11/20/2013
wwang: 9/15/2009
mgross: 3/26/2008
terry: 3/21/2008
alopez: 2/14/2008
alopez: 6/26/2007
alopez: 3/27/2007
terry: 3/23/2007
carol: 10/10/2006
terry: 3/3/2005
alopez: 10/29/2003
terry: 10/29/2003
carol: 2/28/2000
MIM
608901
*RECORD*
*FIELD* NO
608901
*FIELD* TI
#608901 CORONARY HEART DISEASE, SUSCEPTIBILITY TO, 5
;;CHDS5;;
CORONARY ARTERY DISEASE, EARLY-ONSET
read more*FIELD* TX
A number sign (#) is used with this entry because linkage of early-onset
coronary artery disease to chromosome 3q13 can be accounted for, at
least in part, by single-nucleotide polymorphism in the KALRN gene
(604605).
For a discussion of genetic heterogeneity of coronary heart disease
(CHD), see 607339.
MAPPING
To identify genetic factors for coronary artery disease (CAD), Hauser et
al. (2004) performed a genomewide scan in 1,168 persons from 438
families, including 493 affected sib pairs with a documented onset of
CAD before 51 years of age in men and before 56 years of age in women.
They identified a region on chromosome 3q13 that is linked to
early-onset CAD and identified an additional region of interest on 1q25
that also met the criteria for genomewide significance. Chromosome 3q13
achieved a maximum parametric lod score of 2.3 at D3S2460 and a
multipoint lod score of 3.5 near D3S2460 at 140 cM. Using ordered subset
analysis, Shah et al. (2006) found that the linkage evidence for this
peak was significantly increased in families with high HDL (high density
lipoprotein) cholesterol levels. Bowden et al. (2006) also reported
linkage to D3S2460 for coronary artery disease and stroke in the
Diabetes Heart Study, with a similar broad linkage region (multipoint
lod = 2.5).
MOLECULAR GENETICS
To evaluate association under the chromosome 3 linkage peak, Wang et al.
(2007) completed an association-mapping study across the 1-lod-unit-down
supporting interval. The peakwide survey found evidence of association
in SNPs for multiple genes. The strongest associations were found in 3
SNPs from the KALRN gene (604605), especially in patients with
early-onset CAD. Investigation of the KALRN gene found that an intronic
SNP, dbSNP rs9289231, was associated with early-onset CAD in all white
data sets examined (P less than 0.05). In the joint analysis of 332
white, early-onset CAD cases and 546 controls, this SNP was highly
significant (P = 0.00008), with an odds ratio estimate of 2.1.
Furthermore, the risk allele of this SNP was associated with
atherosclerosis burden (P = 0.03) in 145 human aortas. The highly
associated SNP resided in the first intron of an alternative transcript
of the KALRN gene. KALRN is a protein with many functions, including the
inhibition of inducible nitric oxide synthase (INOS; 163730) and guanine
exchange factor activity. KALRN and 2 other associated genes identified
in this study, CDGAP and MYLK (600922), participate in the Rho GTPase
signaling pathway. Wang et al. (2007) concluded that their data
suggested the importance of the KALRN gene and the Rho GTPase signaling
pathway in the pathogenesis of CAD.
*FIELD* RF
1. Bowden, D. W.; Rudock, M.; Ziegler, J.; Lehtinen, A. B.; Xu, J.;
Wagenknecht, L. E.; Herrington, D.; Rich, S. S.; Freedman, B. I.;
Carr, J. J.; Langefeld, C. D.: Coincident linkage of type 2 diabetes,
metabolic syndrome, and measures of cardiovascular disease in a genome
scan of the diabetes heart study. Diabetes 55: 1985-1994, 2006.
2. Hauser, E. R.; Crossman, D. C.; Granger, C. B.; Haines, J. L.;
Jones, C. J. H.; Mooser, V.; McAdam, B.; Winkelmann, B. R.; Wiseman,
A. H.; Muhlestein, J. B.; Bartel, A. G.; Dennis, C. A.; and 22 others
: A genomewide scan for early-onset coronary artery disease in 438
families: the GENECARD study. Am. J. Hum. Genet. 75: 436-447, 2004.
3. Shah, S. H.; Kraus, W. E.; Crossman, D. C.; Granger, C. B.; Haines,
J. L.; Jones, C. J. H.; Mooser, V.; Huang, L.; Haynes, C.; Dowdy,
E.; Vega, G. L.; Grundy, S. M.; Vance, J. M.; Hauser, E. R.: Serum
lipids in the GENECARD study of coronary artery disease identify quantitative
trait loci and phenotypic subsets on chromosomes 3q and 5q. Ann.
Hum. Genet. 70: 738-748, 2006.
4. Wang, L.; Hauser, E. R.; Shah, S. H.; Pericak-Vance, M. A.; Haynes,
C.; Crosslin, D.; Harris, M., II; Nelson, S.; Hale, A. B.; Granger,
C. B.; Haines, J. L.; Jones, C. J. H.; Crossman, D.; Seo, D.; Gregory,
S. G.; Kraus, W. E.; Goldschmidt-Clermont, P. J.; Vance, J. M.: Peakwide
mapping on chromosome 3q13 identifies the kalirin gene as a novel
candidate gene for coronary artery disease. Am. J. Hum. Genet. 80:
650-663, 2007.
*FIELD* CN
Victor A. McKusick - updated: 3/27/2007
*FIELD* CD
Victor A. McKusick: 9/9/2004
*FIELD* ED
wwang: 10/24/2007
terry: 10/23/2007
alopez: 6/26/2007
alopez: 3/27/2007
wwang: 11/8/2006
alopez: 9/10/2004
alopez: 9/9/2004
*RECORD*
*FIELD* NO
608901
*FIELD* TI
#608901 CORONARY HEART DISEASE, SUSCEPTIBILITY TO, 5
;;CHDS5;;
CORONARY ARTERY DISEASE, EARLY-ONSET
read more*FIELD* TX
A number sign (#) is used with this entry because linkage of early-onset
coronary artery disease to chromosome 3q13 can be accounted for, at
least in part, by single-nucleotide polymorphism in the KALRN gene
(604605).
For a discussion of genetic heterogeneity of coronary heart disease
(CHD), see 607339.
MAPPING
To identify genetic factors for coronary artery disease (CAD), Hauser et
al. (2004) performed a genomewide scan in 1,168 persons from 438
families, including 493 affected sib pairs with a documented onset of
CAD before 51 years of age in men and before 56 years of age in women.
They identified a region on chromosome 3q13 that is linked to
early-onset CAD and identified an additional region of interest on 1q25
that also met the criteria for genomewide significance. Chromosome 3q13
achieved a maximum parametric lod score of 2.3 at D3S2460 and a
multipoint lod score of 3.5 near D3S2460 at 140 cM. Using ordered subset
analysis, Shah et al. (2006) found that the linkage evidence for this
peak was significantly increased in families with high HDL (high density
lipoprotein) cholesterol levels. Bowden et al. (2006) also reported
linkage to D3S2460 for coronary artery disease and stroke in the
Diabetes Heart Study, with a similar broad linkage region (multipoint
lod = 2.5).
MOLECULAR GENETICS
To evaluate association under the chromosome 3 linkage peak, Wang et al.
(2007) completed an association-mapping study across the 1-lod-unit-down
supporting interval. The peakwide survey found evidence of association
in SNPs for multiple genes. The strongest associations were found in 3
SNPs from the KALRN gene (604605), especially in patients with
early-onset CAD. Investigation of the KALRN gene found that an intronic
SNP, dbSNP rs9289231, was associated with early-onset CAD in all white
data sets examined (P less than 0.05). In the joint analysis of 332
white, early-onset CAD cases and 546 controls, this SNP was highly
significant (P = 0.00008), with an odds ratio estimate of 2.1.
Furthermore, the risk allele of this SNP was associated with
atherosclerosis burden (P = 0.03) in 145 human aortas. The highly
associated SNP resided in the first intron of an alternative transcript
of the KALRN gene. KALRN is a protein with many functions, including the
inhibition of inducible nitric oxide synthase (INOS; 163730) and guanine
exchange factor activity. KALRN and 2 other associated genes identified
in this study, CDGAP and MYLK (600922), participate in the Rho GTPase
signaling pathway. Wang et al. (2007) concluded that their data
suggested the importance of the KALRN gene and the Rho GTPase signaling
pathway in the pathogenesis of CAD.
*FIELD* RF
1. Bowden, D. W.; Rudock, M.; Ziegler, J.; Lehtinen, A. B.; Xu, J.;
Wagenknecht, L. E.; Herrington, D.; Rich, S. S.; Freedman, B. I.;
Carr, J. J.; Langefeld, C. D.: Coincident linkage of type 2 diabetes,
metabolic syndrome, and measures of cardiovascular disease in a genome
scan of the diabetes heart study. Diabetes 55: 1985-1994, 2006.
2. Hauser, E. R.; Crossman, D. C.; Granger, C. B.; Haines, J. L.;
Jones, C. J. H.; Mooser, V.; McAdam, B.; Winkelmann, B. R.; Wiseman,
A. H.; Muhlestein, J. B.; Bartel, A. G.; Dennis, C. A.; and 22 others
: A genomewide scan for early-onset coronary artery disease in 438
families: the GENECARD study. Am. J. Hum. Genet. 75: 436-447, 2004.
3. Shah, S. H.; Kraus, W. E.; Crossman, D. C.; Granger, C. B.; Haines,
J. L.; Jones, C. J. H.; Mooser, V.; Huang, L.; Haynes, C.; Dowdy,
E.; Vega, G. L.; Grundy, S. M.; Vance, J. M.; Hauser, E. R.: Serum
lipids in the GENECARD study of coronary artery disease identify quantitative
trait loci and phenotypic subsets on chromosomes 3q and 5q. Ann.
Hum. Genet. 70: 738-748, 2006.
4. Wang, L.; Hauser, E. R.; Shah, S. H.; Pericak-Vance, M. A.; Haynes,
C.; Crosslin, D.; Harris, M., II; Nelson, S.; Hale, A. B.; Granger,
C. B.; Haines, J. L.; Jones, C. J. H.; Crossman, D.; Seo, D.; Gregory,
S. G.; Kraus, W. E.; Goldschmidt-Clermont, P. J.; Vance, J. M.: Peakwide
mapping on chromosome 3q13 identifies the kalirin gene as a novel
candidate gene for coronary artery disease. Am. J. Hum. Genet. 80:
650-663, 2007.
*FIELD* CN
Victor A. McKusick - updated: 3/27/2007
*FIELD* CD
Victor A. McKusick: 9/9/2004
*FIELD* ED
wwang: 10/24/2007
terry: 10/23/2007
alopez: 6/26/2007
alopez: 3/27/2007
wwang: 11/8/2006
alopez: 9/10/2004
alopez: 9/9/2004