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Journal of Cell Science, Vol 114, Issue 7 1417-1425, Copyright © 2001 by Company of Biologists
JOURNAL ARTICLES |
LA Maile, J Badley-Clarke and DR Clemmons
CB# 7170, Division of Endocrinology, University of North Carolina, Chapel Hill, NC 27599-7170, USA. endo@med.unc.edu
The disintegrin echistatin inhibits ligand occupancy of the (&agr;)V(&bgr;)3 integrin and reduces Insulin-like growth factor I (IGF-I) stimulated migration, DNA synthesis, and receptor autophosphorylation in smooth muscle cells. This suggests that ligand occupancy of the (&agr;)V(&bgr;)3 receptor is required for full activation of the IGF-I receptor. Transfection of the full-length (&bgr;)3 subunit into CHO cells that have no endogenous (&bgr;)3 and do not migrate in response to IGF-I was sufficient for IGF-I to stimulate migration of these anchorage dependent cells. In contrast, transfection of either of two truncated mutant forms of (&bgr;)3 (terminating at W(715) or E(731)) or a mutant with substitutions for Tyr(747) Tyr(759) (YY) into either CHO or into porcine smooth muscle cells did not restore the capacity of these cells to migrate across a surface in response to IGF-I. This effect was not due to loss of IGF-I receptor autophosphorylation since the response of the receptor to IGF-I was similar in cells expressing either the full-length or any of the mutant forms of the (&bgr;)3 subunit. Echistatin reduced IGF-I receptor phosphorylation in cells expressing the full-length or the YY mutant forms of (&bgr;)3 subunit, but it had no effect in cells expressing either of two truncated forms of (&bgr;)3. A cell-permeable peptide homologous to the C-terminal region of the (&bgr;)3 subunit (amino acids 747-762) reduced IGF-I stimulated migration and receptor autophosphorylation of non-transfected porcine smooth muscle cells. These results demonstrate that the full-length (&bgr;)3 with intact tyrosines at positions 747 and 759 is required for CHO cells to migrate in response to IGF-I. Furthermore, a region of critical amino acids between residues 742-762 is required for echistatin to induce its regulatory effect on receptor phosphorylation. Since the IGF-I receptor does not bind to (&agr;)V(&bgr;)3 the results suggest that specific but distinct regions of the (&bgr;)3 subunit interact with intermediary proteins to facilitate IGF-I stimulated cell migration and echistatin induced inhibition of IGF-I signal transduction.
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