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Caspase-8 Interacts with the p85 Subunit of Phosphatidylinositol 3-Kinase to Regulate Cell Adhesion and Motility

Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia

Requests for reprints: Steven M. Frisch, Mary Babb Randolph Cancer Center, West Virginia University, 1 Medical Center Drive, Campus Box 9300, Morgantown, WV 26506. Phone: 304-293-2980; Fax: 304-293-4667; E-mail: sfrisch{at}hsc.wvu.edu.

Cell migration plays an important role in tumor cell invasion and metastasis. Previously, we reported that caspase-8 contributes to cell migration and adhesion, a novel nonapoptotic function of an established apoptotic factor. Herein, we report that pro-caspase-8 is capable of restoring cell migration/adhesion to caspase-8-null cells, establishing the first biological function of a pro-caspase. The catalytic activity of caspase-8 was not required for cell motility. Stimulation of motility with epidermal growth factor induced the phosphorylation of caspase-8 on tyrosine-380 and the interaction of caspase-8 with the p85 subunit of phosphatidylinositol 3-kinase. Tyrosine-380 was required for the restoration of cell motility and cell adhesion in caspase-8-null cells, demonstrating the importance of the caspase-8–p85 interaction for these nonapoptotic functions. These results suggest that caspase-8 phosphorylation converts it from a proapoptotic factor to a cell motility factor that, through tyrosine-380, interacts with p85, an established cell migration component. [Cancer Res 2007;67(24):11505–9]

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