THE G-PROTEIN-COUPLED RECEPTOR KINASE-2 IS A MICROTUBULE-ASSOCIATED PROTEIN-KINASE THAT PHOSPHORYLATES TUBULIN

The G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine k inase that phosphorylates and desensitizes agonist-occupied G protein- coupled receptors (GPCRs). Here we demonstrate that GRK2 is a microtub ule-associated protein and identify tubulin as a novel GRK2 substrate. GRK2 is associated with microtubules purified from bovine brain, form s a complex with tubulin in cell extracts, and colocalizes with tubuli n in living cells. Furthermore, an endogenous tubulin kinase activity that copurifies with microtubules has properties similar to GRK2 and i s inhibited by anti-GRK2 monoclonal antibodies. Indeed, GRK2 phosphory lates tubulin in vitro with kinetic parameters very similar to those f or phosphorylation of the agonist-occupied beta(2)-adrenergic receptor , suggesting a functionally relevant role for this phosphorylation eve nt. In a cellular environment, agonist occupancy of GPCRs, which leads to recruitment of GRK2 to the plasma membrane and its subsequent acti vation, promotes GRK2-tubulin complex formation and tubulin phosphoryl ation. These findings suggest a novel role for GRK2 as a GPCR signal t ransducer mediating the effects of GPCR activation on the cytoskeleton .