A direct interaction between JNK1 and CrkII is critical for Rac1-induced JNK activation.
CrkII, a cellular homolog of v-crk, belongs to a family of adaptor proteins that play a central role in signal transduction cascades. We demonstrate that CrkII interacts directly with c-Jun N-terminal kinase 1 (JNK1). A proline-rich sequence of JNK1 is critical for the interaction of the kinase with the N-terminal Src homology 3 (SH3) domain of CrkII. JNK1 is localized with CrkII in membrane ruffles of Crk-overexpressing cells in a Rac1-dependent manner. A JNK1 mutant (K340A) that fails to interact with CrkII is defective in Rac/epidermal growth factor-induced activation, but remains responsive to UVC irradiation. Furthermore, CrkII recruits JNK1 to a p130Cas multiprotein complex where it may be activated through a hematopoietic progenitor kinase 1- and mitogen-activated protein kinase kinase 4-dependent pathway. Together, the results presented here argue for a new mechanism of regulation of the JNK pathway through the CrkII-p130Cas adaptor complex.
Girardin
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Unité des Virus Oncogènes, URA CNRS 1644, Institut Pasteur, 25 Rue du Dr Roux, 75724 Paris Cedex 15, France.
Yaniv
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D019943:Amino Acid Substitution; D001665:Binding Sites; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000502:physiology* / Q000528:radiation effects; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014466:Ultraviolet Rays; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D018909:src Homology Domains
D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D011494:Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; D020830:rac1 GTP-Binding Protein