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Vol. 13, Issue 7, 2256-2265, July 2002
*The Division of Vascular Biology, Department of Cell Biology. The
Scripps Research Institute, La Jolla, California 92037; and
§Department of Molecular Cell Biology, Institute of
Molecular Biology, Copenhagen University, Oester Farimagsgade 2A,
DK-1353, Copenhagen K, Denmark
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. To gain
insight into the regulation of integrin activation by Ras
GTPases, 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.
Corresponding author. E-mail address:
ginsberg{at}scripps.edu.
Both authors contributed equally to this work.
Present address: SUGEN, 230 East Grand Avenue,
South San Francisco, CA 94116.
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