Regulation of cell proliferation and migration by TAK1 via transcriptional control of von Hippel-Lindau tumor suppressor.
Skin maintenance and healing after wounding requires complex epithelial-mesenchymal interactions purportedly mediated by growth factors and cytokines. We show here that, for wound healing, transforming growth factor-beta-activated kinase 1 (TAK1) in keratinocytes activates von Hippel-Lindau tumor suppressor expression, which in turn represses the expression of platelet-derived growth factor-B (PDGF-B), integrin beta1, and integrin beta5 via inhibition of the Sp1-mediated signaling pathway in the keratinocytes. The reduced production of PDGF-B leads to a paracrine-decreased expression of hepatocyte growth factor in the underlying fibroblasts. This TAK1 regulation of the double paracrine PDGF/hepatocyte growth factor signaling 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 microspike protrusion, 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 von Hippel-Lindau tumor suppressor. Dysfunctional regulation of TAK1 may contribute to the pathology of non-healing chronic inflammatory wounds and psoriasis.
Tan
Siew Hwey
SH
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Pal
Mintu
M
Tan
Ming Jie
MJ
Wong
Marc Hai Liang
MH
Tam
Fong U
FU
Teo
Jamie Wei Ting
JW
Chong
Han Chung
HC
Tan
Chek Kun
CK
Goh
Yan Yih
YY
Tang
Mark Boon Yang
MB
Cheung
Peter Ching For
PC
Tan
Nguan Soon
NS
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D019899:Paracrine Communication / Q000502:physiology; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D014945:Wound Healing / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099151:MAP Kinase Kinase Kinase 7; C497446:VHL protein, human; C494469:VHL protein, mouse