title: The mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK) acts as a key regulator of keratinocyte terminal differentiation.
abstract: In the skin, epithelial cells undergo a terminal differentiation program leading to the formation of the stratum corneum. Although it is expected that the last phases of this process must be tightly regulated since it results in cell death, the signaling pathways involved in this induction remain ill defined. We now report that a single kinase, the mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK), acts in the epidermis to promote the terminal differentiation of human keratinocytes. In support of this notion, we showed that DLK expression was restricted to the granular layer in situ. In addition, cultured keratinocytes infected with a recombinant adenovirus expressing DLK exhibited morphological and biochemical changes, including a suprabasal localization, altered cell shape, compacted cytoplasm, DNA fragmentation, and the up-regulation of filaggrin, that are reminiscent of a terminally differentiated phenotype. Moreover the expression of wild-type DLK in keratinocytes stimulated transglutaminase activity and the consequent formation of the cornified cell envelope, while a kinase-inactive variant of DLK did not. Together these results identify DLK as a signaling molecule implicated in the regulation of keratinocyte terminal differentiation and cornification.
authors.affiliation: Laboratoire de Recherche des Grand Brûlés/Laboratoire d'Orgnogénèse Experimentale, Centre Hospitalier Affilie Universitaire de Québec pavillon Saint-Sacrement, Québec, Québec G1S 4L8, Canada.
authors.forename: Hubert
authors.initials: H
authors.lastname: Robitaille
authors.forename: Roxanne
authors.initials: R
authors.lastname: Proulx
authors.forename: Karine
authors.initials: K
authors.lastname: Robitaille
authors.forename: Richard
authors.initials: R
authors.lastname: Blouin
authors.forename: Lucie
authors.initials: L
authors.lastname: Germain
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003593:Cytoplasm / Q000378:metabolism; D053938:DNA Fragmentation; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D000091344:Filaggrin Proteins; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007381:Intermediate Filament Proteins / Q000737:chemistry; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases; D008297:Male; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000502:physiology*; D015398:Signal Transduction; D011503:Transglutaminases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D049452:Green Fluorescent Proteins; D011503:Transglutaminases; D017346:Protein Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12