The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration

Dev Cell. 2003 Aug;5(2):257-71. doi: 10.1016/s1534-5807(03)00201-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins
  • Binding Sites
  • Cell Adhesion Molecules / metabolism
  • Cell Line
  • Cell Movement / physiology*
  • Enzyme Activation
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Integrin alpha3beta1 / metabolism*
  • Integrin alpha6beta4 / metabolism*
  • Keratinocytes / cytology
  • Keratinocytes / metabolism*
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Kinase C / metabolism
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Serine / metabolism
  • Signal Transduction / physiology
  • Two-Hybrid System Techniques
  • Tyrosine 3-Monooxygenase / metabolism*
  • Wound Healing / physiology

Substances

  • 14-3-3 Proteins
  • Cell Adhesion Molecules
  • Integrin alpha3beta1
  • Integrin alpha6beta4
  • NF-kappa B
  • Proto-Oncogene Proteins
  • kalinin
  • macrophage stimulating protein
  • Serine
  • Hepatocyte Growth Factor
  • Tyrosine 3-Monooxygenase
  • Phosphatidylinositol 3-Kinases
  • RON protein
  • Receptor Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C