Blockade of v-Src-stimulated tumor formation by the Src homology 3 domain of Crk-associated substrate (Cas).
Crk-associated substrate (Cas) is highly phosphorylated by v-Src and plays a critical role in v-Src-induced cell transformation. In this study, we found that the Src homology (SH) 3 domain of Cas blocked v-Src-stimulated anchorage-independent cell growth, Matrigel invasion, and tumor growth in nude mice. Biochemical analysis revealed that the Cas SH3 domain selectively inhibited v-Src-stimulated activations of AKT and JNK, but not ERK and STAT3. Attenuation of the AKT pathway by the Cas SH3 domain rendered v-Src-transformed cells susceptible to apoptosis. Inhibition of the JNK pathway by the Cas SH3 domain led to suppression of v-Src-stimulated invasion. Taken together, our results indicate that the Cas SH3 domain has an anti-tumor function, which severely impairs the transforming potential of v-Src.
Cheng
Chi-Hung
CH
Section of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan.
Yu
Kuo-Ching
KC
Chen
Hsin-Ling
HL
Chen
Shu-Yi
SY
Huang
Chi-Hui
CH
Chan
Po-Chao
PC
Wung
Chiung-Wha
CW
Chen
Hong-Chen
HC
D016475:3T3 Cells; D000209:Acute-Phase Proteins / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D003094:Collagen; D050719:Crk-Associated Substrate Protein; D004268:DNA-Binding Proteins / Q000378:metabolism; D004338:Drug Combinations; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases; D007797:Laminin; D048670:MAP Kinase Kinase 4; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050717:Retinoblastoma-Like Protein p130; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D018909:src Homology Domains
D000209:Acute-Phase Proteins; D033942:Adaptor Proteins, Vesicular Transport; C493842:Bcar1 protein, mouse; D050719:Crk-Associated Substrate Protein; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D007797:Laminin; D010750:Phosphoproteins; D011506:Proteins; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D050717:Retinoblastoma-Like Protein p130; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C059485:matrigel; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src); D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases