The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration.
Growth factors, integrins, and the extracellular matrix (ECM) are known to play key roles in epidermal wound healing, although the interplay between these proteins is not fully understood. We show that growth factor macrophage stimulating protein (MSP)- and its receptor Ron-mediated PI3K activation in keratinocytes induces phosphorylation of both Ron and alpha6beta4 integrin at specific 14-3-3 binding sites. Consequently, a Ron/alpha6beta4 complex formed via 14-3-3 binding displaces alpha6beta4 from its location at hemidesmosomes (structures supporting cell adhesion) and relocalizes it to lamellipodia. Concomitant activation of alpha3beta1 and keratinocyte spreading/migration on laminin-5 occurs. Further, MSP-dependent beta4 tyrosine phosphorylation evokes p38 and NF-kappaB signaling required for keratinocyte wound closure. Based on these results, we propose a mechanism based on MSP-Ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing.
Santoro
Massimo M
MM
Department of Medical Sciences, University of Piemonte Orientale "A. Avogadro", 28100, Novara, Italy. msantoro@med.unipmn.it
Gaudino
Giovanni
G
Marchisio
Pier Carlo
PC
D048948:14-3-3 Proteins; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology; D000097794:Kalinin
D048948:14-3-3 Proteins; D015815:Cell Adhesion Molecules; D017228:Hepatocyte Growth Factor; D039201:Integrin alpha3beta1; D039161:Integrin alpha6beta4; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases; D012694:Serine; D014446:Tyrosine 3-Monooxygenase; D000097794:Kalinin; C082332:macrophage stimulating protein; C080835:RON protein