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© The Rockefeller University Press, 0021-9525/2000//741 $5.00
The Journal of Cell Biology, Volume 149, Number 3, , 2000 741-754

Matrix Survival Signaling

Eduardo A.C. Almeida^a, Duko Ili^a, Qin Han^a, Christof R. Hauck^c, Fang Jin^a, Hisaaki Kawakatsu^b, David D. Schlaepfer^c, and Caroline H. Damsky^a

^a Department of Stomatology and Department of Anatomy, Department of Medicine, University of California San Francisco, San Francisco, California 94143
^b Lung Biology Center, Department of Medicine, University of California San Francisco, San Francisco, California 94143
^c The Scripps Research Institute, Department of Immunology, La Jolla, California 92037
University of California San Francisco, 513 Parnassus Ave., Box 0512, HSW-604, San Francisco, CA 94143-0512.(415) 502-7338(415) 476-8922

damsky{at}cgl.ucsf.edu

Most transformed cells have lost anchorage and serum dependence for growth and survival. Previously, we established that when serum is absent, fibronectin survival signals transduced by focal adhesion kinase (FAK), suppress p53-regulated apoptosis in primary fibroblasts and endothelial cells (Ili et al. 1998. J. Cell Biol. 143:547–560). The present goals are to identify survival sequences in FAK and signaling molecules downstream of FAK required for anchorage-dependent survival of primary fibroblasts. We report that binding of the SH3 domain of p130Cas to proline-rich region 1 of FAK is required to support survival of fibroblasts on fibronectin when serum is withdrawn. The FAK–p130Cas complex activates c-Jun NH2-terminal kinase (JNK) via a Ras/Rac1/Pak1/MAPK kinase 4 (MKK4) pathway. Activated (phospho-) JNK colocalizes 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 matrix if serum factors are provided. In that case, we confirm work of others that 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 survival pathway documented herein. Thus, survival signals from extracellular matrix and serum are transduced by FAK via two distinct pathways.

Key Words: fibroblast • anchorage-dependent survival • focal contacts • MAP kinase • apoptosis

© 2000 The Rockefeller University Press

Eduardo A.C. Almeida and Duko Ili contributed equally to this work.

Abbreviations used in this paper: Cas, p130Cas; DN, dominant-negative; ECM, extracellular matrix; ERK, extracellular signal–regulated kinase; ES, embryo stem; FAK, focal adhesion kinase; FAT, focal adhesion targeting; FN, fibronectin; FRNK, FAK-related nonkinase; GFP, green fluorescent protein; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated, dual-action kinase; MEK, MAPK kinase; MKK4, MAPK kinase 4; PI3-kinase, phosphatidylinositol 3'-kinase; PKB, protein kinase B; PR-1, proline-rich region 1; RSF, rabbit synovial fibroblasts; SD, substrate domain; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling.

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