The p38-MAPK/SAPK pathway is required for human keratinocyte migration on dermal collagen

J Invest Dermatol. 2001 Dec;117(6):1601-11. doi: 10.1046/j.0022-202x.2001.01608.x.


Human keratinocyte motility plays an important role in the re-epithelialization of human skin wounds. The wound bed over which human keratinocytes migrate is rich in extracellular matrices, such as fibrin, fibronectin, and collagen, and serum factors, such as platelet-derived growth factor and transforming growth factor beta 1. Extracellular matrices and the serum factors bind to cell surface receptors and initiate a cascade of intracellular signaling events that regulate cell migration. In this study, we identified an intracellular signaling pathway that mediates collagen- driven motility of human keratinocytes. Pharmaco logic inhibition of the activation of p38-alpha and p38-beta mitogen-activated protein kinase activation potently blocked collagen-driven human keratinocyte migration. Transfection of the same keratinocytes with the kinase-negative mutants of p38-alpha or p38-beta mitogen-activated protein kinase markedly inhibited keratinocyte migration on collagen. Attachment of keratinocytes to collagen activated p38 mitogen- activated protein kinase, as well as p44/p42 ERKs. Interestingly, activation of the p38 mitogen-activated protein kinase cascade by overexpressing the constitutively active MKK3 and MKK6, MKK3b(E) and MKK6b(E), could neither initiate migration in the absence of collagen nor enhance collagen-driven migration. This study provides evidence that the p38-MAPK/SAPK pathway is necessary, but insufficient, for mediating human keratinocyte migration on collagen.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line, Transformed
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Collagen Type I / pharmacology
  • Dermis / cytology
  • Extracellular Matrix / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases*
  • Keratinocytes / cytology*
  • Keratinocytes / enzymology*
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 6
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism
  • Transfection
  • p38 Mitogen-Activated Protein Kinases


  • Collagen Type I
  • Protein-Tyrosine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 6
  • MAP2K3 protein, human
  • MAP2K6 protein, human
  • Mitogen-Activated Protein Kinase Kinases