Synergistic effect of focal adhesion kinase overexpression and hepatocyte growth factor stimulation on cell transformation.
Although an elevated level of focal adhesion kinase (FAK) has been observed in a variety of invasive human tumors, forced expression of FAK alone in cultured cells does not cause them to exhibit transformed phenotypes. Therefore, the role of FAK in oncogenic transformation remains unclear. In this study, we have demonstrated that FAK overexpression in Madin-Darby canine kidney epithelial cells rendered them susceptible to transformation by hepatocyte growth factor (HGF). Using various FAK mutants, we found that the simultaneous bindings of Src and p130(cas) were required for FAK to potentiate cell transformation. Expression of FAK-related nonkinase, kinase-deficient Src, or the Src homology 3 domain of p130(cas), which respectively serve as dominant negative versions of FAK, Src, and p130(cas), apparently reversed the transformed phenotypes of FAK-overexpressed cells upon HGF stimulation. Moreover, FAK overexpression was able to enhance HGF-elicited signals, leading to sustained activation of ERK, JNK, and AKT, which could be prevented by the expression of the Src homology 3 domain of p130(cas). Taken together, our results indicate that the synergistic effect of FAK overexpression and HGF stimulation leads to cell transformation and implicate a critical role of p130(cas) in this process.
Chan
Po-Chao
PC
Department of Life Sciences and the Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
Liang
Chun-Chi
CC
Yu
Kuo-Ching
KC
Chang
Ming-Chen
MC
Ho
William L
WL
Chen
Bor-Huah
BH
Chen
Hong-Chen
HC
D019943:Amino Acid Substitution; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003094:Collagen; D004285:Dogs; D004338:Drug Combinations; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007797:Laminin; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011509:Proteoglycans; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011994:Recombinant Proteins; C059485:matrigel; D017228:Hepatocyte Growth Factor; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human