7yqe

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Current revision (09:43, 9 October 2024) (edit) (undo)
 
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7yqe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7yqe OCA], [https://pdbe.org/7yqe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7yqe RCSB], [https://www.ebi.ac.uk/pdbsum/7yqe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7yqe ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7yqe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7yqe OCA], [https://pdbe.org/7yqe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7yqe RCSB], [https://www.ebi.ac.uk/pdbsum/7yqe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7yqe ProSAT]</span></td></tr>
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== Disease ==
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<div style="background-color:#fffaf0;">
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[https://www.uniprot.org/uniprot/SRC_HUMAN 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.[https://www.uniprot.org/uniprot/KISSR_HUMAN 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).<ref>PMID:23643382</ref> The disease is caused by variants affecting the gene represented in this entry.
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== Publication Abstract from PubMed ==
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== Function ==
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Osteoclasts are over-activated as we age, which results in bone loss. Src deficiency in mice leads to severe osteopetrosis due to a functional defect in osteoclasts, indicating that Src function is essential in osteoclasts. G-protein-coupled receptors (GPCRs) are the targets for approximately 35% of approved drugs but it is still unclear how GPCRs regulate Src kinase activity. Here, we reveal that GPR54 activation by its natural ligand Kisspeptin-10 (Kp-10) causes Dusp18 to dephosphorylate Src at Tyr 416. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase at its proline/arginine-rich motif in its C terminus. We show that Kp-10 binding to Gpr54 leads to the up-regulation of Dusp18. Kiss1, Gpr54 and Dusp18 knockout mice all exhibit osteoclast hyperactivation and bone loss, and Kp-10 abrogated bone loss by suppressing osteoclast activity in vivo. Therefore, Kp-10/Gpr54 is a promising therapeutic target to abrogate bone resorption by Dusp18-mediated Src dephosphorylation.
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[https://www.uniprot.org/uniprot/SRC_HUMAN 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'.<ref>PMID:3093483</ref> <ref>PMID:2498394</ref> <ref>PMID:7853507</ref> <ref>PMID:8759729</ref> <ref>PMID:8755529</ref> <ref>PMID:11389730</ref> <ref>PMID:12615910</ref> <ref>PMID:14585963</ref> <ref>PMID:16186108</ref> <ref>PMID:18586953</ref> <ref>PMID:19419966</ref> <ref>PMID:20100835</ref> <ref>PMID:21309750</ref> <ref>PMID:21411625</ref> <ref>PMID:22710723</ref> [https://www.uniprot.org/uniprot/KISSR_HUMAN 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.<ref>PMID:15020672</ref>
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Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.,Li Z, Yang X, Fu R, Wu Z, Xu S, Jiao J, Qian M, Zhang L, Wu C, Xie T, Yao J, Wu Z, Li W, Ma G, You Y, Chen Y, Zhang HK, Cheng Y, Tang X, Wu P, Lian G, Wei H, Zhao J, Xu J, Ai L, Siwko S, Wang Y, Ding J, Song G, Luo J, Liu M, Xiao J Nat Commun. 2024 Feb 12;15(1):1300. doi: 10.1038/s41467-024-44852-9. PMID:38346942<ref>PMID:38346942</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7yqe" style="background-color:#fffaf0;"></div>
== References ==
== References ==
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Current revision

Structure of human SRC regulatory domains in complex with the C-terminal PRRP motifs of GPR54.

PDB ID 7yqe

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