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Published 29 April 2002. doi:10.1083/jcb.200111065
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© The Rockefeller University Press, 0021-9525/2002/4/481 $5.00
The Journal of Cell Biology, Volume 157, Number 3, April 29, 2002 481-492

Article

 Defective Rac-mediated proliferation and survival after targeted mutation of the ß1 integrin cytodomain

Emilio Hirsch1,2, Laura Barberis1, Mara Brancaccio1, Ornella Azzolino1, Dazhong Xu5, John M. Kyriakis5, Lorenzo Silengo1,2, Filippo G. Giancotti6, Guido Tarone1,2, Reinhard Fässler3,4 and Fiorella Altruda1,2

1 Dipartimento di Genetica, Biologia, e Biochimica, Università di Torino, 10126 Torino, Italy
2 Experimental Medicine Research Center, San Giovanni Battista Hospital, 10126 Torino, Italy
3 Max-Planck Institute for Biochemistry, 8285 Martinsried, Germany
4 Department of Experimental Pathology, Lund University Hospital, S-222 85 Lund, Sweden
5 Diabetes Research Laboratory, Medical Services, Massachusetts General Hospital, Boston, MA 02129
6 Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Address correspondence to Emilio Hirsch, Dipartimento di Genetica, Biologia, e Biochimica, Università di Torino, via Santena 5 bis, 10126 Torino, Italy. Tel.: 39-011-670-6680. Fax: 39-011-670-6547. E-mail: emilio.hirsch{at}unito.it

Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of ß1 integrin leads to defective proliferation and survival both in vivo and in vitro. Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-PI3K-Akt and Rac-JNK signaling pathways. Expression in homozygous MEFs of a constitutively active form of Rac is able to rescue proliferation, survival, and JNK activation. Moreover, although showing normal Erk phosphorylation, mutant cells fail to display Erk nuclear translocation upon fibronectin adhesion. However, expression of the constitutively activated form of Rac restores Erk nuclear localization, suggesting that adhesion-dependent Rac activation is necessary to integrate signals directed to promote MAPK activity. Altogether, our data provide the evidence for an epistatic interaction between the ß1 integrin cytoplasmic domain and Rac, and indicate that this anchorage-dependent signaling pathway is crucial for cell growth control.

Key Words: integrin; cytodomain; RAC; MAPK; proliferation


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