Phosphorylation and regulation of a G protein-coupled receptor by protein kinase CK2.
We demonstrate a role for protein kinase casein kinase 2 (CK2) in the phosphorylation and regulation of the M3-muscarinic receptor in transfected cells and cerebellar granule neurons. On agonist occupation, specific subsets of receptor phosphoacceptor sites (which include the SASSDEED motif in the third intracellular loop) are phosphorylated by CK2. Receptor phosphorylation mediated by CK2 specifically regulates receptor coupling to the Jun-kinase pathway. Importantly, other phosphorylation-dependent receptor processes are regulated by kinases distinct from CK2. We conclude that G protein-coupled receptors (GPCRs) can be phosphorylated in an agonist-dependent fashion by protein kinases from a diverse range of kinase families, not just the GPCR kinases, and that receptor phosphorylation by a defined kinase determines a specific signalling outcome. Furthermore, we demonstrate that the M3-muscarinic receptor can be differentially phosphorylated in different cell types, indicating that phosphorylation is a flexible regulatory process where the sites that are phosphorylated, and hence the signalling outcome, are dependent on the cell type in which the receptor is expressed.
Torrecilla
Ignacio
I
Department of Cell Physiology and Pharmacology and Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Leicester LE1 9HN, England, UK.
Spragg
Elizabeth J
EJ
Poulin
Benoit
B
McWilliams
Phillip J
PJ
Mistry
Sharad C
SC
Blaukat
Andree
A
Tobin
Andrew B
AB
D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D016384:Consensus Sequence; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D043587:Receptor, Muscarinic M3 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism
D043587:Receptor, Muscarinic M3; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D051552:beta-Adrenergic Receptor Kinases