UniProt functional annotation for P34947



	UniProt functional annotation for P34947

UniProt code: P34947.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Serine/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}.

Catalytic activity: Reaction=[G-protein-coupled receptor] + ATP = [G-protein-coupled receptor]-phosphate + ADP + H(+); Xref=Rhea:RHEA:12008, Rhea:RHEA- COMP:11260, Rhea:RHEA-COMP:11261, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43176, ChEBI:CHEBI:68546, ChEBI:CHEBI:456216; EC=2.7.11.16;

Activity regulation: Inhibited by calmodulin with an IC(50) of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid. {ECO:0000269|PubMed:9218466}.

Subunit: Interacts with ST13 (via the C-terminus 303-319 AA) (PubMed:21728385). Interacts with TP53/p53 (PubMed:20124405). Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) (PubMed:19661922). Interacts with HDAC5 (By similarity). Interacts with GIT1 (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q62833, ECO:0000250|UniProtKB:Q8VEB1, ECO:0000269|PubMed:19661922, ECO:0000269|PubMed:20124405, ECO:0000269|PubMed:21728385}.

Subcellular location: Cytoplasm. 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.

Tissue specificity: Highest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney. {ECO:0000269|PubMed:7685906}.

Induction: Overexpressed during heart failure. {ECO:0000269|PubMed:8381058}.

Ptm: Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity. {ECO:0000269|PubMed:8144599}.

Polymorphism: Variant 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.

Similarity: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Serine/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}.


Catalytic activity:		Reaction=[G-protein-coupled receptor] + ATP = [G-protein-coupled receptor]-phosphate + ADP + H(+); Xref=Rhea:RHEA:12008, Rhea:RHEA- COMP:11260, Rhea:RHEA-COMP:11261, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43176, ChEBI:CHEBI:68546, ChEBI:CHEBI:456216; EC=2.7.11.16;
Activity regulation:		Inhibited by calmodulin with an IC(50) of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid. {ECO:0000269\|PubMed:9218466}.
Subunit:		Interacts with ST13 (via the C-terminus 303-319 AA) (PubMed:21728385). Interacts with TP53/p53 (PubMed:20124405). Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) (PubMed:19661922). Interacts with HDAC5 (By similarity). Interacts with GIT1 (By similarity). {ECO:0000250, ECO:0000250\|UniProtKB:Q62833, ECO:0000250\|UniProtKB:Q8VEB1, ECO:0000269\|PubMed:19661922, ECO:0000269\|PubMed:20124405, ECO:0000269\|PubMed:21728385}.
Subcellular location:		Cytoplasm. 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.
Tissue specificity:		Highest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney. {ECO:0000269\|PubMed:7685906}.
Induction:		Overexpressed during heart failure. {ECO:0000269\|PubMed:8381058}.
Ptm:		Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity. {ECO:0000269\|PubMed:8144599}.
Polymorphism:		Variant 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.
Similarity:		Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. {ECO:0000305}.