CNK1 is a scaffold protein that regulates Src-mediated Raf-1 activation.
Raf-1 is a regulator of cellular proliferation, differentiation, and apoptosis. Activation of the Raf-1 kinase activity is tightly regulated and involves targeting to the membrane by Ras and phosphorylation by various kinases, including the tyrosine kinase Src. Here we demonstrate that the connector enhancer of Ksr1, CNK1, mediates Src-dependent tyrosine phosphorylation and activation of Raf-1. CNK1 binds preactivated Raf-1 and activated Src and forms a trimeric complex. CNK1 regulates the activation of Raf-1 by Src in a concentration-dependent manner typical for a scaffold protein. Down-regulation of endogenously expressed CNK1 by small inhibitory RNA interferes with Src-dependent activation of ERK. Thus, CNK1 allows cross-talk between Src and Raf-1 and is essential for the full activation of Raf-1.
Ziogas
Algirdas
A
Institute of Medical Virology, University of Zurich, Gloriastrasse 30, CH-8006 Zurich, Switzerland.
Moelling
Karin
K
Radziwill
Gerald
G
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D019281:Dimerization; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C500833:CNKSR1 protein, human; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; D016392:Proto-Oncogene Proteins pp60(c-src); D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases