We examined the role of c-FLIP in the motility of HeLa cells. A small interfering RNA (siRNA directed against c-FLIP inhibited the adhesion and motility of the cells without affecting their growth rate. The long form of c-FLIP (c-FLIPL), but not the short form (c-FLIPs), enhanced adhesion and motility. Downregulation of c-FLIPL -with siRNA decreased phosphorylation of FAK and ERK, while overexpression of c-FLIP, increased their phosphorylation. Overexpression of FAK activated ERK, and enhanced the motility of HeLa cells. FRNK, an inhibitory fragment of FAK, inhibited ERK and decreased motility. Inhibition of ERK also significantly suppressed c-FLIPL-promoted motility. Inhibition of ROCK by Y27632 suppressed the c-FLIPL-promoted motility by reducing phosphorylalion of FAK in ERK. Overexpression of c-FLIPL increased the expression and secretion of MMP-9, and inhibition of MMP-9 by Iloniaslat reduced c-FLIPL- promoted cell motilily. A caspase-like domain (amino acids 222-376) was found to be necessary for the c-FLIPL-promoted cell motility. We conclude that c-FLIPL promotes the motility of HeLa cells by activating FAK and ERK, and increasing MMP-9 expression.
|Number of pages||12|
|Journal||Molecules and Cells|
|State||Published - 30 Apr 2008|