Role of LIM kinases in normal and psoriatic human epidermis.
We present evidence that LIM kinases can control cell adhesion and compaction in human epidermis. LIMK2 is expressed in the epidermal basal layer and signals downstream of the GTPase Rac1 to promote extracellular matrix adhesion and inhibit terminal differentiation. Conversely, LIMK1 is expressed in the upper granular layers and phosphorylates and inhibits cofilin. Expression of LIMK1 is lost in psoriatic lesions and other skin disorders characterized by lack of cell compaction in the differentiating cell layers. In psoriatic lesions down-regulation of LIMK1 correlates with up-regulation of Myc. Expression of constitutively active cofilin or Myc in reconstituted human epidermis blocks cell compaction. Overexpression of LIMK1 leads to down-regulation of Myc, whereas inhibition of Rho kinase, an upstream activator of LIMK1, stimulates Myc expression. Inhibition of Myc by LIMK1 is via inhibition of Stat3 phosphorylation, because constitutively active cofilin or inhibition of Rho kinase results in Stat3 phosphorylation and increased Myc levels, whereas dominant negative Stat3 abolishes the effect. In conclusion, we have uncovered a novel antagonistic relationship between the LIMK1/phosphocofilin and Myc/Stat3 pathways in the differentiating layers of human epidermis and propose that down-regulation of LIMK1 contributes to one of the pathological features of psoriatic epidermal lesions.
Keratinocyte Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom.
Masaru
M
Honma
Salvador Aznar
SA
Benitah
Fiona M
FM
Watt
D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology; D054461:Lim Kinases; D009154:Mutation; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism; D011565:Psoriasis / Q000201:enzymology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation
D051338:Cofilin 1; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases