Anchorage-independent phosphorylation of p130(Cas) protects lung adenocarcinoma cells from anoikis.
The regulation and function of the signaling adaptor protein p130(Cas) in tumor cell anchorage-independent survival, or anoikis resistance, were investigated in human lung adenocarcinoma cells. The tyrosine phosphorylation and function of p130(Cas) during cell detachment were analyzed in tumor cells and compared with that of normal epithelial cells. Cell detachment trigged rapid dephosphorylation of p130(Cas) in the nontumorigenic and anoikis-sensitive normal epithelial cells, but had no effect on the tyrosine phosphorylation of p130(Cas) in the anoikis-resistant lung adenocarcinoma cells. Further analysis revealed that the total tyrosine kinase activities associated with p130(Cas) in the lung tumor cells are anchorage-independent and are significantly higher than that in the normal cells, in which the p130(Cas)-associated tyrosine kinase activities are anchorage-dependent. Analysis of two known p130(Cas)-associated tyrosine kinases FAK and Src indicated that the regulation of tyrosine phosphorylation of FAK and Src are altered in the tumor cells. Inhibition of Src specifically abolished phosphorylation of p130(Cas) and induced anoikis. Furthermore, overexpression of dominant-negative forms of p130(Cas) also induced apoptosis. Taken together, these data suggest that p130(Cas) mediates a cell survival signal from cell-matrix interaction. Alterations in tumor cells that lead to constitutive phosphorylation of p130(Cas) can prevent cells from anoikis, hence contribute to tumor cell anchorage independence and metastasis.
Wei
Lin
L
Pulmonary Center, Department of Biochemistry, Boston University Medical Center, Boston, Massachusetts 02118, USA.
Yang
Yu
Y
Zhang
Xin
X
Yu
Qiang
Q
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D023102:Anoikis; D017209:Apoptosis; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D002470:Cell Survival; D050719:Crk-Associated Substrate Protein; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D010750:Phosphoproteins; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D019061:src-Family Kinases