Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways.
Rho family GTPases act as molecular switches to control a variety of cellular responses, including cytoskeletal rearrangements, changes in gene expression, and cell transformation. In the active, GTP-bound state, Rho interacts with an ever-growing number of effector molecules, which promote distinct biochemical pathways. Here, we describe the isolation of hCNK1, the human homologue of Drosophila connector enhancer of ksr, as an effector for Rho. hCNK1 contains several protein-protein interaction domains, and Rho interacts with one of these, the PH domain, in a GTP-dependent manner. A mutant hCNK1, which is unable to bind to Rho, or depletion of endogenous hCNK1 by using RNA interference inhibits Rho-induced gene expression via serum response factor but has no apparent effect on Rho-induced stress fiber formation, suggesting that it acts as a specific effector for transcriptional, but not cytoskeletal, activation pathways. Finally, hCNK1 associates with Rhophilin and RalGDS, Rho and Ras effector molecules, respectively, suggesting that it acts as a scaffold protein to mediate cross talk between the two pathways.
Jaffe
Aron B
AB
MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, Cancer Research UK Oncogene and Signal Transduction Group, and Department of Biochemistry, University College London, London WC1E 6BT, United Kingdom.
Aspenström
Pontus
P
Hall
Alan
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism; D014158:Transcription, Genetic; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C115753:CNK protein, Drosophila; D002352:Carrier Proteins; D029721:Drosophila Proteins; D026362:Serum Response Factor; D020726:ral Guanine Nucleotide Exchange Factor; C097916:rhophilin; D017346:Protein Serine-Threonine Kinases; D015689:Oncogene Protein p21(ras); D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein