Functional roles of transforming growth factor activated Kinase-1 (TAK1) in skin wound healing

Abstract

Healing wound and maintaining new skin growth requires complex interactions of the epithelium and mesenchyme purportedly mediated by growth factors and cytokines. We show here that during wound healing, TAK1 activates von Hippel-Lindau tumor suppressor (pVHL) expression in keratinocytes which, in turn, represses the expression of PDGF-B and, integrins beta1 and beta5 via inhibition of the Sp1-mediated transcription. The reduced production of PDGF-B leads to a paracrine decrease in expression of hepatocyte growth factor (HGF) in the underlying fibroblasts, as well as reduced epidermal proliferation. This TAK1 regulation of the dual PDGF/HGF paracrine signaling system can regulate keratinocyte cell proliferation and is required for proper wound healing. Strikingly, TAK1 deficiency enhances cell migration. TAK1-deficient keratinocytes displayed lamellipodia formation with distinct microspikes protrusions, which was associated with an elevated expression of integrins beta1 and beta5, and sustained activation of cdc42, Rac1 and RhoA. Our findings provide evidence for a novel homeostatic control of keratinocyte proliferation and migration, mediated via TAK1 regulation of pVHL. Dysfunctional regulation of TAK1 may contribute to the pathology of chronic inflammatory wounds and psoriasis.