title: Direct evidence that PKCα positively regulates wound re-epithelialization: correlation with changes in desmosomal adhesiveness.
abstract: Non-healing wounds cause considerable patient morbidity and represent a significant economic burden. Central to wound repair is re-epithelialization, a crucial process involving the modulation of cell adhesion to allow keratinocyte migration to cover the exposed underlying tissues. The cellular mechanisms regulating the earliest stages of re-epithelialization are unclear. We present the first direct evidence that protein kinase Cα (PKCα) plays an important role in regulating wound re-epithelialization. In PKCα(-/-) mice re-epithelialization is delayed, while in novel bitransgenic mice over-expressing constitutively active PKCα it is accelerated. These effects are not due to changes in keratinocyte proliferation, apoptosis or intrinsic cell motility. Instead, they correlate with changes in desmosomal adhesiveness, delay being preceded by retained desmosomal hyper-adhesiveness and acceleration with a rapid switch to desmosomal Ca(2+) -dependence. We demonstrate mechanistic conservation in acute human wounds where PKCα localizes to wound edge desmosomes, which become Ca(2+) -dependent. However, in chronic wounds PKCα remains cytoplasmic and desmosomes fail to switch from the hyper-adhesive state. These results throw new mechanistic light on the earliest stages of wound re-epithelialization and suggest activation of PKCα as a new therapeutic strategy for non-healing wounds.
authors.affiliation: Faculty of Life Sciences, University of Manchester, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Thomason
authors.forename: Nichola H
authors.initials: NH
authors.lastname: Cooper
authors.forename: David M
authors.initials: DM
authors.lastname: Ansell
authors.forename: Maybo
authors.initials: M
authors.lastname: Chiu
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Merrit
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hardman
authors.forename: David R
authors.initials: DR
authors.lastname: Garrod
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D003896:Desmosomes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005838:Genotype; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D017354:Point Mutation; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha; D002118:Calcium