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A more recent version of this article appeared on July 1, 2002
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Submitted on October 5, 2001
Revised on February 7, 2002
Accepted on April 1, 2002
1 The Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (present address: SUGEN, 230 East Grand Avenue, South San Francisco, CA 94116)
2 The Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
3 Department of Molecular Cell Biology, Institute of Molecular Biology, Copenhagen University, Oester Farimagsgade 2A, DK-1353, Copenhagen K, Denmark
* Corresponding author. E-mail address: ginsberg{at}scripps.edu.
The rapid modulation of ligand-binding affinity ("activation") is a central property of the integrin family of cell adhesion receptors. The Ras family of small GTP-binding proteins and their downstream effectors are key players in regulating integrin activation. H-Ras can suppress integrin activation in fibroblasts via its downstream effector kinase, Raf-1. In contrast, to H-Ras, a closely related small GTP-binding protein R-Ras has the opposite activity, and promotes integrin activation. In order to gain insight into the regulation of integrin activation by Ras GTP'ases we created a series of H-Ras/R-Ras chimeras. We found that a 35 amino acid stretch of H-Ras was required for full suppressive activity. Furthermore, the suppressive chimeras were weak activators of the ERK1/2 MAP kinase pathway, suggesting that the suppression of integrin activation may be independent of the activation of the bulk of ERK MAP kinase. Additional data demonstrating that the ability of H-Ras or Raf-1 to suppress integrin activation was unaffected by inhibition of bulk ERK1/2 MAP kinase activation supported this hypothesis. Thus, the suppression of integrin activation is a Raf kinase induced regulatory event that can be mediated independently of bulk activation of the ERK MAP-kinase pathway.
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