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Vol. 9, Issue 8, 2287-2303, August 1998
Departments of
*Stomatology and
The ubiquitously expressed Na-H exchanger NHE1 functions in
regulating intracellular pH and cell volume. NHE1 activity is stimulated by hormones, growth factors, and activation of
integrin receptors. We recently determined that NHE1 activity
is also stimulated by activation of the low molecular weight GTPase
RhoA and that increases in NHE1 activity are necessary for
RhoA-induced formation of actin stress fibers. We now show that
NHE1 acts downstream of RhoA to modulate initial steps in
integrin signaling for the assembly of focal adhesions.
Adhesion of CCL39 fibroblasts on fibronectin was markedly
delayed in the presence of the NHE inhibitor ethylisopropylamiloride. In mutant PS120 cells, derived
from CCL39 fibroblasts but lacking NHE1, adhesion was also
delayed but was rescued in PS120 cells stably expressing NHE1.
In the absence of NHE1 activity, cell spreading was inhibited, and the
accumulation of integrins, paxillin, and vinculin at focal
contacts was impaired. Additionally, tyrosine phosphorylation of
p125FAK induced by integrin clustering was also
impaired. Inactivation of RhoA with C3 transferase and inhibition of
the Rho-kinase p160ROCK with the pyridine derivative Y-27632 completely
abolished activation of NHE1 by integrins but not by
platelet-derived growth factor. These findings indicate that NHE1 acts
downstream of RhoA to contribute a previously unrecognized critical
signal to proximal events in integrin-induced cytoskeletal
reorganization.
Surgery, University
of California, San Francisco, California 94143
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