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J. Biol. Chem., Vol. 280, Issue 9, 8004-8015, March 4, 2005

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Integrin 64-erbB2 Complex Inhibits Haptotaxis by Up-regulating E-cadherin Cell-Cell Junctions in Keratinocytes^*

Edith Hintermann, Neng Yang, Deirdre O'Sullivan¶, Jonathan M. G. Higgins||, and Vito Quaranta**

From the Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, the Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232-2175, the ^¶Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and the ^||Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Keratinocyte integrins 64 and 31 bind laminin-5, a component of basement membranes. We previously demonstrated that in keratinocytes, haptotactic migration on laminin-5 was stimulated by anti-1 integrin-activating antibody TS2/16, whereas antibodies to 6 and 4, respectively, blocked TS2/16-induced, 31-dependent migration. Moreover, 64-associated haptotaxis inhibition was linked to a phosphatidylinositol 3-kinase (PI3K) pathway and required erbB2 activation. erbB2, the ligand-less member of the epidermal growth factor receptor family, was shown to form a complex with the hemidesmosomal integrin 64. Here, we demonstrate that 64 inhibitory effects on haptotaxis are abolished by an anti-E-cadherin antibody, which interferes with cell-cell adhesion. Furthermore, antibodies to 6 and 4 stimulated adhesion to an E-cadherin-Fc recombinant protein. In addition, anti-6/4 antibodies increased colony size in plated cells, stimulated cell-cell aggregation, and up-regulated E-cadherin localization to cell-cell contacts. These effects were abolished when erbB2 or PI3K were blocked. These results indicate that stimulation of 64 increases E-cadherin-mediated cell-cell adhesion and that this mechanism depends on erbB2 activation. The molecule that links 64 with E-cadherin may be the small GTPase cdc42, an effector of PI3K, because dominant-negative cdc42 abolished the inhibitory effect of anti-6/4 antibodies and increased basal migration, whereas constitutively active cdc42 prevented the TS2/16-induced increase in haptotaxis. These findings suggest a model whereby 64 can augment cell-cell adhesion and slow down haptotaxis over laminin-5 and point to the 64-erbB2 heterodimer as an important signaling complex for the formation of cohesive keratinocyte layers.

Received for publication, June 7, 2004 , and in revised form, November 10, 2004.

In memory of Dr. Neng Yang, a passionate scientist and sophisticated man.

^* This work was supported by a fellowship of the Swiss National Science Foundation for Medical-Biological Grants (to E.H.), by the Crohn's and Colitis Foundation of America (to J.M.G.H.) and by NIH grants CA 47858 and GM46902 (to V.Q.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Cancer Biology, School of Medicine, Vanderbilt University, 771 PRB, 23rd and Pierce Ave., Nashville, TN 37232-2175. Tel.: 615-936-2868; Fax: 615-936-2911; E-mail: vito.quaranta{at}vanderbilt.edu.

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