title: Integrin alpha6beta4-erbB2 complex inhibits haptotaxis by up-regulating E-cadherin cell-cell junctions in keratinocytes.
abstract: 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.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Edith
authors.initials: E
authors.lastname: Hintermann
authors.forename: Neng
authors.initials: N
authors.lastname: Yang
authors.forename: Deirdre
authors.initials: D
authors.lastname: O'Sullivan
authors.forename: Jonathan M G
authors.initials: JM
authors.lastname: Higgins
authors.forename: Vito
authors.initials: V
authors.lastname: Quaranta
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry; D002450:Cell Communication; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D019281:Dimerization; D005109:Extracellular Matrix / Q000378:metabolism; D005799:Genes, Dominant; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D039161:Integrin alpha6beta4 / Q000378:metabolism / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008024:Ligands; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation; D014945:Wound Healing; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D000097794:Kalinin
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D005982:Glutathione Transferase; D039161:Integrin alpha6beta4; D016023:Integrins; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020764:cdc42 GTP-Binding Protein; D000097794:Kalinin