Matrix survival signaling: From fibronectin via focal adhesion kinase to c-Jun NH2-terminal kinase

Most transformed cells have lost anchorage and serum dependence for growth and survival. Previously, we established that when serum is absent, fibrone ctin survival signals transduced by focal adhesion kinase (FAK), suppress p 53-regulated apoptosis in primary fibroblasts and endothelial cells (IliC c t al., 1998, J. Cell Biol. 143:547-560), The present goals are to identify survival sequences in FAK and signaling molecules downstream of FAK require d for anchorage-dependent survival of primary fibroblasts. We report that b inding of the SH3 domain of p130Cas to proline-rich region 1 of FAK is requ ired to support survival of fibroblasts on fibronectin when serum is withdr awn. The FAK-p130Cas complex activates c-Jun NH2-terminal kinase (JNK) via a Ras/Rac1/Pak1/MAPK kinase 4 (MKK4) pathway. Activated (phospho-) JNK colo calizes with FAK in focal adhesions of fibroblasts cultured on fibronectin, which supports their survival, but not in fibroblasts cultured on collagen , which does not. Cells often survive in the absence of extracellular matri x if serum factors are provided. In that case, we confirm work of others th at survival signals are transduced by FAK, phosphatidylinositol 3'-kinase ( PI3-kinase), and Akt/protein kinase B (PKB). However, when serum is absent, PI3-kinase and Akt/PKB are not involved in the fibronectin-FAK-JNK surviva l pathway documented herein. Thus, survival signals from extracellular matr ix and serum are transduced by FAK via two distinct pathways.