Cleavage of p130Cas in anoikis.
p130Cas is a multifunctional signaling adaptor protein. It integrates and relays signals generated from a variety of extracellular stimuli and regulates a number of cellular activities including cell death. In this study, we analyzed the regulation and function of p130Cas in anoikis, a type of apoptosis caused by disruption of cell-matrix interactions. We found that p130Cas was specifically cleaved during anoikis in anoikis-sensitive epithelial cells, but not in anoikis-resistant tumor cells. There is a close correlation between p130Cas cleavage and anoikis. Furthermore, we found that the cleavage of p130Cas, as well as another focal adhesion component FAK, is different from that of caspase substrate PARP and spectrin. Although caspases and calpain were found to be involved in the cleavage of p130Cas, there appear to be other unidentified proteases that are mainly responsible for the cleavage of p130Cas, particularly at the early stage of anoikis. Overexpression of the p130Cas cleavage product induced apoptosis. Taken together, these data suggest that there are novel proteases involved in the cleavage of p130Cas during anoikis, which may be functionally involved in the onset of anoikis. p130Cas may have a dual role in the regulation of anoikis. On one hand, it mediates a survival signal from cell-matrix interactions when cells are attached to the extracellular matrix. On the other hand, it participates in executing cell death when cell-matrix interactions are disrupted. These observations provide new insights into the understanding of the function of p130Cas and the molecular mechanism of anoikis.
Wei
Lin
L
Pulmonary Center, Department of Medicine, and Department of Biochemistry, Boston University Medical Center, Boston, Massachusetts 02118, USA.
Yang
Yu
Y
Zhang
Xing
X
Yu
Qiang
Q
D000818:Animals; D023102:Anoikis; D002154:Calpain / Q000494:pharmacology; D020169:Caspases / Q000494:pharmacology; D018929:Cell Culture Techniques; D050719:Crk-Associated Substrate Protein; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130; D014407:Tumor Cells, Cultured
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D002154:Calpain; D020169:Caspases