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Sci. STKE, 9 December 2003
Vol. 2003, Issue 212, p. tw473
[DOI: 10.1126/stke.2122003TW473]

EDITORS' CHOICE

CROSSTALK Killing Two Kinases with One Inhibitor

RKIP (Raf kinase inhibitor protein) associates with and inhibits the enzymatic activity of the protein kinase Raf, an upstream kinase in MAPK (mitogen-activated protein kinase) signaling cascades. RKIP appears to mediate crosstalk with other pathways, and phosphorylation of RKIP by protein kinase C (PKC) relieves inhibition of Raf-1. Now Lorenz et al. report a more extensive role of RKIP in coordinating signaling through G protein-coupled receptors (GPCRs). Their experiments show that RKIP is also an inhibitor of GRK-2 (G protein-coupled receptor kinase 2), a kinase that diminishes signaling through GPCRs by uncoupling them from G proteins and promoting their internalization. In transfected cells and various native tissues, the amount of RKIP associated with GRK-2 was increased after stimulation of appropriate GPCRs and correlated with phosphorylation of RKIP at a site phosphorylated by PKC. Such phosphorylation appeared to be necessary for inhibition of GRK-2 because mutants of RKIP lacking the phosphorylated serine residue were not effective inhibitors of GRK-2. The increased association of RKIP with GRK-2 coincided with reduced association of RKIP with Raf-1. Thus, in unstimulated cells, RKIP appears to hold Raf-1 in an inactive state. Depletion of RKIP from cardiomyocytes by electroporation in the presence of specific antibodies inhibited signaling and contraction in response to stimulation of β-adrenergic receptors. The authors propose that phosphorylation of RKIP by PKC after stimulation of GPCRs then contributes in two ways to GPCR signaling: Release of RKIP from Ras-1 promotes signaling through MAPK and the released protein then inhibits GRK-1, thereby preventing desensitization and internalization of GPCRs.

K. Lorenz, M. J. Lohse, U. Quitterer, Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 426, 574-579 (2003). [Online Journal]

Citation: Killing Two Kinases with One Inhibitor. Sci. STKE 2003, tw473 (2003).


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