Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Binding Sites
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Cell Membrane / enzymology
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Enzyme Activation
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Epidermal Growth Factor / pharmacology
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HeLa Cells
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Humans
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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MAP Kinase Signaling System / physiology*
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MAP Kinase Signaling System / radiation effects
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Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase*
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Mitogen-Activated Protein Kinases / chemistry
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Mutagenesis, Site-Directed
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Protein Kinases / chemistry
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Protein Kinases / metabolism*
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Proto-Oncogene Proteins c-crk
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Proto-Oncogene Proteins*
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Transfection
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Ultraviolet Rays
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rac1 GTP-Binding Protein / metabolism*
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src Homology Domains
Substances
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-crk
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Recombinant Proteins
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Epidermal Growth Factor
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Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase
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rac1 GTP-Binding Protein