7yqe

Structural highlights

Disease

SRC_HUMAN Note=SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells.KISSR_HUMAN Idiopathic central precocious puberty;Normosmic congenital hypogonadotropic hypogonadism. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in KISS1R as well as in other HH-associated genes including FGFR1 and IL17RD (PubMed:23643382).^[1] The disease is caused by variants affecting the gene represented in this entry.

Function

SRC_HUMAN Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1. Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors. Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation. Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of ADRBK1, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor. Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus. Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase. Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr-128'.^{[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]} KISSR_HUMAN Receptor for metastin (kisspeptin-54 or kp-54), a C-terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein that suppresses metastases in malignant melanomas and in some breast carcinomas without affecting tumorigenicity. The metastasis suppressor properties may be mediated in part by cell cycle arrest and induction of apoptosis in malignant cells. The receptor is essential for normal gonadotropin-released hormone physiology and for puberty. The hypothalamic KiSS1/KISS1R system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood. The receptor is also probably involved in the regulation and fine-tuning of trophoblast invasion generated by the trophoblast itself. Analysis of the transduction pathways activated by the receptor identifies coupling to phospholipase C and intracellular calcium release through pertussis toxin-insensitive G(q) proteins.^[17]

References

1. ↑ Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008. PMID:23643382 doi:http://dx.doi.org/10.1016/j.ajhg.2013.04.008
2. ↑ Rosen N, Bolen JB, Schwartz AM, Cohen P, DeSeau V, Israel MA. Analysis of pp60c-src protein kinase activity in human tumor cell lines and tissues. J Biol Chem. 1986 Oct 15;261(29):13754-9. PMID:3093483
3. ↑ Cartwright CA, Kamps MP, Meisler AI, Pipas JM, Eckhart W. pp60c-src activation in human colon carcinoma. J Clin Invest. 1989 Jun;83(6):2025-33. PMID:2498394 doi:http://dx.doi.org/10.1172/JCI114113
4. ↑ David-Pfeuty T, Nouvian-Dooghe Y. Highly specific antibody to Rous sarcoma virus src gene product recognizes nuclear and nucleolar antigens in human cells. J Virol. 1995 Mar;69(3):1699-713. PMID:7853507
5. ↑ Rabinowich H, Manciulea M, Metes D, Sulica A, Herberman RB, Corey SJ, Whiteside TL. Physical and functional association of Fc mu receptor on human natural killer cells with the zeta- and Fc epsilon RI gamma-chains and with src family protein tyrosine kinases. J Immunol. 1996 Aug 15;157(4):1485-91. PMID:8759729
6. ↑ Grano M, Galimi F, Zambonin G, Colucci S, Cottone E, Zallone AZ, Comoglio PM. Hepatocyte growth factor is a coupling factor for osteoclasts and osteoblasts in vitro. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7644-8. PMID:8755529
7. ↑ Giglione C, Gonfloni S, Parmeggiani A. Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm. Eur J Biochem. 2001 Jun;268(11):3275-83. PMID:11389730
8. ↑ Miyazaki T, Neff L, Tanaka S, Horne WC, Baron R. Regulation of cytochrome c oxidase activity by c-Src in osteoclasts. J Cell Biol. 2003 Mar 3;160(5):709-18. PMID:12615910 doi:10.1083/jcb.200209098
9. ↑ Taniyama Y, Weber DS, Rocic P, Hilenski L, Akers ML, Park J, Hemmings BA, Alexander RW, Griendling KK. Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates focal adhesions. Mol Cell Biol. 2003 Nov;23(22):8019-29. PMID:14585963
10. ↑ Yang K, Kim JH, Kim HJ, Park IS, Kim IY, Yang BS. Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation. J Biol Chem. 2005 Nov 25;280(47):39058-66. Epub 2005 Sep 26. PMID:16186108 doi:10.1074/jbc.M506921200
11. ↑ Jeulin C, Seltzer V, Bailbe D, Andreau K, Marano F. EGF mediates calcium-activated chloride channel activation in the human bronchial epithelial cell line 16HBE14o-: involvement of tyrosine kinase p60c-src. Am J Physiol Lung Cell Mol Physiol. 2008 Sep;295(3):L489-96. doi:, 10.1152/ajplung.90282.2008. Epub 2008 Jun 27. PMID:18586953 doi:10.1152/ajplung.90282.2008
12. ↑ Johnsen IB, Nguyen TT, Bergstroem B, Fitzgerald KA, Anthonsen MW. The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-elicited antiviral signaling. J Biol Chem. 2009 Jul 10;284(28):19122-31. doi: 10.1074/jbc.M808233200. Epub 2009, May 6. PMID:19419966 doi:10.1074/jbc.M808233200
13. ↑ Goh YM, Cinghu S, Hong ET, Lee YS, Kim JH, Jang JW, Li YH, Chi XZ, Lee KS, Wee H, Ito Y, Oh BC, Bae SC. Src kinase phosphorylates RUNX3 at tyrosine residues and localizes the protein in the cytoplasm. J Biol Chem. 2010 Mar 26;285(13):10122-9. doi: 10.1074/jbc.M109.071381. Epub 2010, Jan 25. PMID:20100835 doi:10.1074/jbc.M109.071381
14. ↑ Chan W, Sit ST, Manser E. The Cdc42-associated kinase ACK1 is not autoinhibited but requires Src for activation. Biochem J. 2011 Apr 15;435(2):355-64. doi: 10.1042/BJ20102156. PMID:21309750 doi:10.1042/BJ20102156
15. ↑ Wang Y, Cao H, Chen J, McNiven MA. A direct interaction between the large GTPase dynamin-2 and FAK regulates focal adhesion dynamics in response to active Src. Mol Biol Cell. 2011 May;22(9):1529-38. doi: 10.1091/mbc.E10-09-0785. Epub 2011, Mar 16. PMID:21411625 doi:10.1091/mbc.E10-09-0785
16. ↑ Zhang P, Guo A, Possemato A, Wang C, Beard L, Carlin C, Markowitz SD, Polakiewicz RD, Wang Z. Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14. Oncogene. 2012 Jun 18. doi: 10.1038/onc.2012.220. PMID:22710723 doi:10.1038/onc.2012.220
17. ↑ Bilban M, Ghaffari-Tabrizi N, Hintermann E, Bauer S, Molzer S, Zoratti C, Malli R, Sharabi A, Hiden U, Graier W, Knöfler M, Andreae F, Wagner O, Quaranta V, Desoye G. Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts. J Cell Sci. 2004 Mar 15;117(Pt 8):1319-28. PMID:15020672 doi:10.1242/jcs.00971