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Molecular and Cellular Biology, August 2001, p. 5082-5093, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5082-5093.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of Insulin Receptor Substrate 1 (IRS-1) and IRS-2 as Signaling Intermediates in the alpha 6beta 4 Integrin-Dependent Activation of Phosphoinositide 3-OH Kinase and Promotion of Invasion

Leslie M. Shaw*

Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Received 17 November 2000/Returned for modification 16 January 2001/Accepted 30 April 2001

Expression of the alpha 6beta 4 integrin increases the invasive potential of carcinoma cells by a mechanism that involves activation of phosphoinositide 3-OH kinase (PI3K). In the present study, we investigated the signaling pathway by which the alpha 6beta 4 integrin activates PI3K. Neither the alpha 6 nor the beta 4 cytoplasmic domain contains the consensus binding motif for PI3K, pYMXM, indicating that additional proteins are likely to be involved in the activation of this lipid kinase by the alpha 6beta 4 integrin. We identified insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the activation of PI3K by the alpha 6beta 4 integrin. IRS-1 and IRS-2 are cytoplasmic adapter proteins that do not contain intrinsic kinase activity but rather function by recruiting proteins to surface receptors, where they organize signaling complexes. Ligation of the alpha 6beta 4 receptor promotes tyrosine phosphorylation of IRS-1 and IRS-2 and increases their association with PI3K, as determined by coimmunoprecipitation. Moreover, we identified a tyrosine residue in the cytoplasmic domain of the beta 4 subunit, Y1494, that is required for alpha 6beta 4-dependent phosphorylation of IRS-2 and activation of PI3K in response to receptor ligation. Most importantly, Y1494 is essential for the ability of the alpha 6beta 4 integrin to promote carcinoma invasion. Taken together, these results imply a key role for the IRS proteins in the alpha 6beta 4-dependent promotion of carcinoma invasion.

* Mailing address: Department of Pathology, Beth Israel Deaconess Medical Center-RN227, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-1430. Fax: (617) 667-3616. E-mail: lshaw{at}caregroup.harvard.edu.

Molecular and Cellular Biology, August 2001, p. 5082-5093, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5082-5093.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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