UniProt functional annotation for P43249



	UniProt functional annotation for P43249

UniProt code: P43249.

Organism: Bos taurus (Bovine).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae; Bovinae; Bos.

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 (Beta-2 adrenergic receptor), 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) (By similarity). {ECO:0000250, ECO:0000269|PubMed:8120045}.

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 (By similarity). {ECO:0000250}.

Subunit: Interacts with ST13 (via the C-terminus 303-319 AA) (By similarity). Interacts with TP53/p53 (By similarity). Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) (By similarity). Interacts with HDAC5 (By similarity). Interacts with GIT1 (By similarity). {ECO:0000250|UniProtKB:P34947, ECO:0000250|UniProtKB:Q62833, ECO:0000250|UniProtKB:Q8VEB1}.

Subcellular location: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. Cell membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. 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 (By similarity). {ECO:0000250}.

Tissue specificity: Highest levels in lung, heart, retina, lingual epithelium. Very little in brain, liver, kidney. {ECO:0000269|PubMed:8120045}.

Ptm: Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity. {ECO:0000269|PubMed:8120045}.

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:		Bos taurus (Bovine).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae; Bovinae; Bos.



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 (Beta-2 adrenergic receptor), 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) (By similarity). {ECO:0000250, ECO:0000269\|PubMed:8120045}.


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 (By similarity). {ECO:0000250}.
Subunit:		Interacts with ST13 (via the C-terminus 303-319 AA) (By similarity). Interacts with TP53/p53 (By similarity). Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) (By similarity). Interacts with HDAC5 (By similarity). Interacts with GIT1 (By similarity). {ECO:0000250\|UniProtKB:P34947, ECO:0000250\|UniProtKB:Q62833, ECO:0000250\|UniProtKB:Q8VEB1}.
Subcellular location:		Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. Cell membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. 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 (By similarity). {ECO:0000250}.
Tissue specificity:		Highest levels in lung, heart, retina, lingual epithelium. Very little in brain, liver, kidney. {ECO:0000269\|PubMed:8120045}.
Ptm:		Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity. {ECO:0000269\|PubMed:8120045}.
Similarity:		Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. {ECO:0000305}.