MAPK SIGNALING PDE, A Link Between Receptors and MAPK?

Abstract: The inhibitory subunit of the rod cyclic guanosine monophosphate phosphodiesterase (PDE) is expressed in several nonphotoreceptive cells, including lung, kidney, heart, testis, and smooth muscle and the human embryonic kidney cell line HEK293. Wan et al. found that expression of antisense for PDE inhibited epidermal growth factor (EGF)-stimulated or thrombin-stimulated phosphorylation of the p44 and p42 mitogen-activated protein kinases (p42^MAPK and p44^MAPK). Furthermore, overexpression of either the rod or cone forms of PDE enhanced p42/p44^MAPK phosphorylation stimulated by these two ligands. EGF receptors are tyrosine kinase growth factor receptors, and the thrombin receptor is a G protein-coupled receptor (GPCR). Internalization of both receptor tyrosine kinases and GPCRs may be important for efficient MAPK activation. Internalization of the receptors may involve G protein-coupled receptor kinase 2 (GRK2). PDE is a substrate for GRK2, and phosphorylation of PDE is enhanced by the addition of Gß in vitro. Expression of a form of PDE not phosphorylated by GRK2 inhibited EGF-stimulated phosphorylation of p42/p44^MAPK, suggesting a link between GRK2 and coupling of EGF to MAPK. In thrombin-treated cells, PDE coprecipitates with dynamin II, a guanosine triphosphatase (GTPase) involved in clathrin-mediated endocytosis, and may stimulate dyanmin II's GTPase activity, further supporting a link between receptor internalization, PDE, and MAPK signaling.

K. F. Wan, B. S. Sambi, M. Frame, R. Tate, N. J. Pyne, The inhibitory subunit of the type 6 retinal cyclic guanosine monophosphate phosphodiesterase is a novel intermediate regulating p42/p44 mitogen-activated protein kinase signaling in human embryonic kidney 293 cells. J. Biol. Chem. 276, 37802-27808 (2001). [Abstract] [Full Text]