Reduced G-protein-coupled-receptor kinase 2 activity results in impairmentof osteoblast function

Rapid phosphorylation of many G-protein-coupled receptors (GPCRs) by G-prot ein-coupled receptor kinases (GRKs) accompanies stimulus-driven desensitiza tion. Recent evidence suggests that GRKs and their associated arresting pro teins, beta-arrestins, function as essential elements in the GPCR-mediated mitogen-activated protein (MAP) kinase signaling cascade, We investigated t he interaction between GRKs and MAP kinase activation by growth factors in UMR 106-H5 osteoblastic cells stably expressing a dominant negative mutant of GRK2 (K220R), Expression of K220R in osteoblastic cells results in reduc ed cellular proliferation, both basally and in response to Insulin-like gro wth factor-1 (IGF-1), and blunting of IGF-1- and EGF-induced MAP kinase act ivation, Reduced MAP kinase activation is not associated with alterations i n IGF-l-receptor autophosphorylation. Both a constitutively active Ras muta nt and PR IA Fully activate MAP kinase in K220R cells. We found that disrup tion of the GRK2 gene results in: (1) reduced osteoblast proliferation in r esponse to growth factors, and (2) impaired receptor tyrosine kinase activa tion of mitogenic signaling pathways. Thus, GRK2 may regulate growth factor responsiveness in osteoblasts by modulating multiprotein complex formation following receptor tyrosine kinase activation. (C) 2000 by Elsevier Scienc e Inc. All rights reserved.