Integrin alpha6beta4-erbB2 complex inhibits haptotaxis by up-regulating E-cadherin cell-cell junctions in keratinocytes.

Hintermann E, Yang N, O'Sullivan D, Higgins JM, Quaranta V
J Biol Chem. 2005 280 (9): 8004-15

PMID: 15579904 · DOI:10.1074/jbc.M406301200

Keratinocyte integrins alpha6beta4 and alpha3beta1 bind laminin-5, a component of basement membranes. We previously demonstrated that in keratinocytes, haptotactic migration on laminin-5 was stimulated by anti-beta1 integrin-activating antibody TS2/16, whereas antibodies to alpha6 and beta4, respectively, blocked TS2/16-induced, alpha3beta1-dependent migration. Moreover, alpha6beta4-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 alpha6beta4. Here, we demonstrate that alpha6beta4 inhibitory effects on haptotaxis are abolished by an anti-E-cadherin antibody, which interferes with cell-cell adhesion. Furthermore, antibodies to alpha6 and beta4 stimulated adhesion to an E-cadherin-Fc recombinant protein. In addition, anti-alpha6/beta4 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 alpha6beta4 increases E-cadherin-mediated cell-cell adhesion and that this mechanism depends on erbB2 activation. The molecule that links alpha6beta4 with E-cadherin may be the small GTPase cdc42, an effector of PI3K, because dominant-negative cdc42 abolished the inhibitory effect of anti-alpha6/beta4 antibodies and increased basal migration, whereas constitutively active cdc42 prevented the TS2/16-induced increase in haptotaxis. These findings suggest a model whereby alpha6beta4 can augment cell-cell adhesion and slow down haptotaxis over laminin-5 and point to the alpha6beta4-erbB2 heterodimer as an important signaling complex for the formation of cohesive keratinocyte layers.

MeSH Terms (27)

Cadherins cdc42 GTP-Binding Protein Cell Adhesion Cell Adhesion Molecules Cell Communication Cell Line Cell Line, Tumor Cell Movement Dimerization Extracellular Matrix Genes, Dominant Glutathione Transferase Humans Immunoprecipitation Integrin alpha6beta4 Integrins Keratinocytes Ligands Microscopy, Fluorescence Neoplasms Phosphatidylinositol 3-Kinases Protein Binding Receptor, ErbB-2 Retroviridae Signal Transduction Up-Regulation Wound Healing

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