9ckr

Structural highlights

Function

GRK5_HUMAN 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).^{[1] [2] [3] [4] [5]}

References

1. ↑ Barthet G, Carrat G, Cassier E, Barker B, Gaven F, Pillot M, Framery B, Pellissier LP, Augier J, Kang DS, Claeysen S, Reiter E, Baneres JL, Benovic JL, Marin P, Bockaert J, Dumuis A. Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling. EMBO J. 2009 Sep 16;28(18):2706-18. Epub 2009 Aug 6. PMID:19661922 doi:http://dx.doi.org/emboj2009215
2. ↑ Chen M, Philipp M, Wang J, Premont RT, Garrison TR, Caron MG, Lefkowitz RJ, Chen W. G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J Biol Chem. 2009 Dec 11;284(50):35040-8. doi: 10.1074/jbc.M109.047456. Epub 2009, Oct 2. PMID:19801552 doi:10.1074/jbc.M109.047456
3. ↑ Baameur F, Morgan DH, Yao H, Tran TM, Hammitt RA, Sabui S, McMurray JS, Lichtarge O, Clark RB. Role for the regulator of G-protein signaling homology domain of G protein-coupled receptor kinases 5 and 6 in beta 2-adrenergic receptor and rhodopsin phosphorylation. Mol Pharmacol. 2010 Mar;77(3):405-15. doi: 10.1124/mol.109.058115. Epub 2009 Dec , 28. PMID:20038610 doi:http://dx.doi.org/10.1124/mol.109.058115
4. ↑ Chen X, Zhu H, Yuan M, Fu J, Zhou Y, Ma L. G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis. J Biol Chem. 2010 Apr 23;285(17):12823-30. doi: 10.1074/jbc.M109.094243. Epub, 2010 Feb 2. PMID:20124405 doi:http://dx.doi.org/10.1074/jbc.M109.094243
5. ↑ Barker BL, Benovic JL. G protein-coupled receptor kinase 5 phosphorylation of hip regulates internalization of the chemokine receptor CXCR4. Biochemistry. 2011 Aug 16;50(32):6933-41. doi: 10.1021/bi2005202. Epub 2011 Jul, 12. PMID:21728385 doi:http://dx.doi.org/10.1021/bi2005202