| First Author | Jadali A | Year | 2010 |
| Journal | J Biol Chem | Volume | 285 |
| Issue | 30 | Pages | 23387-97 |
| PubMed ID | 20463010 | Mgi Jnum | J:165839 |
| Mgi Id | MGI:4838519 | Doi | 10.1074/jbc.M110.105619 |
| Citation | Jadali A, et al. (2010) Protein kinase D is implicated in the reversible commitment to differentiation in primary cultures of mouse keratinocytes. J Biol Chem 285(30):23387-97 |
| abstractText | Although commitment to epidermal differentiation is generally considered to be irreversible, differentiated keratinocytes (KCs) have been shown to maintain a regenerative potential and to reform skin epithelia when placed in a suitable environment. To obtain insights into the mechanism of reinitiation of this proliferative response in differentiated KCs, we examined the reversibility of commitment to Ca(2+)-induced differentiation. Lowering Ca(2+) concentration to micromolar levels triggered culture-wide morphological and biochemical changes, as indicated by derepression of cyclin D1, reinitiation of DNA synthesis, and acquisition of basal cell-like characteristics. These responses were inhibited by Goedecke 6976, an inhibitor of protein kinase D (PKD) and PKCalpha, but not with GF109203X, a general inhibitor of PKCs, suggesting PKD activation by a PKC-independent mechanism. PKD activation followed complex kinetics with a biphasic early transient phosphorylation within the first 6 h, followed by a sustained and progressive phosphorylation beginning at 24 h. The second phase of PKD activation was followed by prolonged ERK1/2 signaling and progression to DNA synthesis in response to the low Ca(2+) switch. Specific knockdown of PKD-1 by RNA interference or expression of a dominant negative form of PKD-1 did not have a significant effect on normal KC proliferation and differentiation but did inhibit Ca(2+)-mediated reinitiation of proliferation and reversion in differentiated cultures. The present study identifies PKD as a major regulator of a proliferative response in differentiated KCs, probably through sustained activation of the ERK-MAPK pathway, and provides new insights into the process of epidermal regeneration and wound healing. |
