MGP Database

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MGP001300

UniProt Annotations

Entry Information
Gene NameG protein-coupled receptor kinase 5
Protein EntryGRK5_HUMAN
UniProt IDP34947
SpeciesHuman
Comments
Comment typeDescription
Catalytic ActivityATP + [G-protein-coupled receptor] = ADP + [G- protein-coupled receptor] phosphate.
Enzyme RegulationInhibited by calmodulin with an IC(50) of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid. {ECO:0000269|PubMed:9218466}.
FunctionSerine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein- coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70- interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2- mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G- protein-coupled receptor, LRP6 during Wnt signaling (in vitro). {ECO:0000269|PubMed:19661922, ECO:0000269|PubMed:19801552, ECO:0000269|PubMed:20038610, ECO:0000269|PubMed:20124405, ECO:0000269|PubMed:21728385}.
InductionOverexpressed during heart failure. {ECO:0000269|PubMed:8381058}.
InteractionP97288:Htr4 (xeno); NbExp=8; IntAct=EBI-7149314, EBI-7149283;
PolymorphismVariant Leu-41 variant is rare in European-Americans individuals but common in African-Americans individuals (40% of the African-American individuals studied carry at least one allele). Variant leu-41 is associated with decreased mortality in African-Americans with heart failure or cardiac ischemia.
PtmAutophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity. {ECO:0000269|PubMed:18669648}.
SimilarityBelongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. {ECO:0000305}.
SimilarityContains 1 AGC-kinase C-terminal domain. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 RGS domain. {ECO:0000255|PROSITE- ProRule:PRU00171}.
Subcellular LocationCytoplasm. Nucleus. Cell membrane; Peripheral membrane protein. Note=Predominantly localized at the plasma membrane; targeted to the cell surface through the interaction with phospholipids. Nucleus localization is regulated in a GPCR and Ca(2+)/calmodulin-dependent fashion.
SubunitInteracts with ST13 (via the C-terminus 303-319 AA). Interacts with TP53/p53. Interacts with HTR4 (via C-terminus 330- 346 AA); this interaction is promoted by 5-HT (serotonin). Interacts with HDAC5 (By similarity). {ECO:0000250}.
Tissue SpecificityHighest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney. {ECO:0000269|PubMed:7685906}.
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