The adaptor protein Crk connects multiple cellular stimuli to the JNK signaling pathway.
c-Jun N-terminal kinases (JNKs) are potently activated by a number of cellular stimuli. Small GTPases, in particular Rac, are responsible for initiating the activation of the JNK pathways. So far, the signals leading from extracellular stimuli to the activation of Rac have remained elusive. Recent studies have demonstrated that the Src homology 2 (SH2)- and Src homology 3 (SH3)-containing adaptor protein Crk is capable of activating JNK when ectopically expressed. We found here that transient expression of Crk induces JNK activation, and this activation was dependent on both the SH2- and SH3-domains of Crk. Expression of p130(Cas) (Cas), a major binding protein for the Crk SH2-domain, also induced JNK activation, which was blocked by the SH2-mutant of Crk. JNK activation by Cas and Crk was effectively blocked by a dominant-negative form of Rac, suggesting for a linear pathway from the Cas-Crk-complex to the Rac-JNK activation. Many of the stimuli that activate the Rac-JNK pathway enhance engagement of the Crk SH2-domain. JNK activation by these stimuli, such as epidermal growth factor, integrin ligand binding and v-Src, was efficiently blocked by dominant-negative mutants of Crk. A dominant-negative form of Cas in turn blocked the integrin-, but not epidermal growth factor - nor v-Src-mediated JNK activation. Together, these results demonstrate an important role for Crk in connecting multiple cellular stimuli to the Rac-JNK pathway, and a role for the Cas-Crk complex in integrin-mediated JNK activation.
Dolfi
F
F
La Jolla Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA.
Garcia-Guzman
M
M
Ojaniemi
M
M
Nakamura
H
H
Matsuda
M
M
Vuori
K
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D050719:Crk-Associated Substrate Protein; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014162:Transfection; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C493841:BCAR1 protein, human; C082869:CRKL protein; D050719:Crk-Associated Substrate Protein; D016023:Integrins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011994:Recombinant Proteins; D050717:Retinoblastoma-Like Protein p130; D004815:Epidermal Growth Factor; D015688:Oncogene Protein pp60(v-src); D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases