title: Crk activation of JNK via C3G and R-Ras.
abstract: v-crk is an oncogene identified originally in CT10 chicken tumor virus. C3G, a guanine nucleotide exchange factor (GEF) for Rap1 and R-Ras, is postulated to transduce the oncogenic signal of v-Crk to c-Jun kinase (JNK). We have found that R-Ras, but not Rap1, mediates JNK activation by v-Crk in 293T and NIH 3T3 cells. Constitutively activated R-Ras, R-Ras(Val-38), but not Rap1(Val-12), activated JNK, as did the constitutively active H-Ras(Val-12) or Rac1(Val-12). v-Crk activation of JNK was inhibited by a dominant-negative mutant of R-Ras, R-Ras(Asn-43). JNK activation by R-Ras(Val-38) was inhibited by a dominant-negative mutant of mixed lineage kinase 3. Among six GEFs for Ras-family G proteins, mSos1, Ras-GRF, C3G, CalDAG-GEFI, Ras-GRP/CalDAG-GEFII, and Epac/cAMP-GEFI, GEFs for either H-Ras or R-Ras activated JNK and c-Jun-dependent transcription. CalDAG-GEFI and Epac/cAMP-GEFI, both of which are GEFs specific for Rap1, did not activate JNK or c-Jun-dependent transcription. These results demonstrate that R-Ras, but not Rap1, is the downstream effector of C3G to stimulate JNK. Finally, we found that expression of the dominant-negative R-Ras mutant induced flat reversion of NIH 3T3 cells transformed by v-Crk, suggesting that R-Ras-dependent JNK activation is critical for the transformation by v-Crk.
authors.affiliation: Department of Pathology, Research Institute, International Medical Center of Japan, Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Y
authors.initials: Y
authors.lastname: Ohba
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: N
authors.initials: N
authors.lastname: Otsuka
authors.forename: A M
authors.initials: AM
authors.lastname: Graybiel
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Matsuda
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism* / Q000502:physiology*; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D050736:Oncogene Protein v-crk; D010957:Plasmids; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D015398:Signal Transduction; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism* / Q000502:physiology*
chemical_list: D018076:DNA, Complementary; D020735:Guanine Nucleotide-Releasing Factor 2; D050736:Oncogene Protein v-crk; D015682:Retroviridae Proteins, Oncogenic; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C085929:RRAS protein, human; C513254:Rras protein, mouse; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins