G protein-coupled receptors (GPCRs) are the largest family of signaling proteins in animals. Among mammals, elephants hold the record with >3400 GPCR subtypes. GRKs belong to the AGC kinase super-family(named for protein kinases A, G, and C discovered earlier). Unlike the other AGC kinases, such as PKA or PKC, GRKs do not have a consensus phosphorylation site, but appear to phosphorylate various serines and threonines in the C-terminus and other cytoplasmic GPCR elements regardless of their sequence context. GRKs of the GRK2/3 subfamily apparently phosphorylate different serines and threonines than ubiquitous members of GRK4 subfamily, GRK5/6, as was directly demonstrated with some GPCRs or deduced from different functional consequences of this phosphorylation in case of other receptors. Another peculiarity of GRKs  is that they are not activated by small molecules or the phosphorylation of the activation loop, but by physical interaction with activated GPCRs. GRKs have been reported to phosphorylate and thus regulate via phosphorylation numerous non-GPCR substrates, including receptor tyrosine kinases, single transmembrane domain serine/threonine kinases, death receptors, toll-like receptors, transcription factors, various adapter proteins, cytosolic, nuclear and cytoskeletal proteins.


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