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Vol. 10, Issue 9, 2861-2878, September 1999
1-Integrin Function by Epidermal Growth
Factor and Heregulin-
Has Distinct Requirements for erbB2 but a
Similar Dependence on Phosphoinositide 3-OH Kinase


and
§
*Department of Laboratory Medicine and Pathology,
Integrins and growth factor receptors are important
participants in cellular adhesion and migration. The EGF receptor
(EGFR) family of tyrosine kinases and the
Center for Immunology,
Cancer Center,
University of Minnesota, Minneapolis, Minnesota 55455
1-integrin
adhesion receptors are of particular interest, given the implication
for their involvement in the initiation and progression of
tumorigenesis. We used adhesion and chemotaxis assays to further
elucidate the relationship between these two families of transmembrane
signaling molecules. Specifically, we examined
integrin-mediated adhesive and migratory characteristics of the
metastatic breast carcinoma cell line MDA-MB-435 in response to
stimulation with growth factors that bind to and activate the EGFR or
erbB3 in these cells. Although ligand engagement of the EGFR stimulated
modest
1-dependent increases in cell adhesion and motility,
heregulin-
(HRG
) binding to the erbB3 receptor initiated rapid
and potent induction of breast carcinoma cell adhesion and migration
and required dimerization of erbB3 with erbB2. Pharmacologic inhibitors
of phosphoinositide 3-OH kinase (PI 3-K) or transient expression of
dominant negative forms of PI 3-K inhibited both EGF- and
HRG
-mediated adhesion and potently blocked HRG
- and EGF-induced
cell motility. Our results illustrate the critical role of PI 3-K
activity in signaling pathways initiated by the EGFR or erbB3 to
up-regulate
1-integrin function.
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