Role for FAK expression in adhesion and metastasis of EL4 lymphoma cells.

Abstract

The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to phorbol 12‐myristate 13‐acetate (PMA). In sensitive cells, PMA causes Erk MAPK activation and Erk‐mediated growth arrest; both are mediated by expression of Ras‐GRP. In resistant cells, PMA induces a low levels of Erk activation, without growth arrest. A relatively unexplored aspect of the phenotypes is that resistant EL4 cells are more adherent to culture substrate than are sensitive cells. The roles of the protein tyrosine kinase, focal adhesion kinase (FAK), in EL4 cell phenotype was therefore examined. FAK is expressed only in PMA‐resistant (or intermediate phenotype) cells, correlating with enhanced substrate adherence, while the FAK‐related kinase Pyk2 is more highly expressed in PMA‐sensitive cells. These differences in protein expression are reflected in mRNA levels. A series of studies indicated that FAK does not play a major role in modulating PMA‐induced Erk activation. However, FAK expression enhances cell migration and invasion. In an experimental metastasis model using syngeneic mice, only PMA‐resistant EL4 cells that express FAK form liver tumors. The results demonstrate that the PMA‐resistant phenotype is required for metastasis of this lymphoma cell line. These studies also suggest that, in combination with other factors, FAK expression promotes metastasis of EL4 cells. Supported by NIH CA94144.