Opposing growth regulatory roles of protein kinase D isoforms in human keratinocytes.

摘要: PKD is a family of three serine/threonine kinases (PKD-1, -2, and -3) involved in the regulation diverse biological processes including proliferation, migration, secretion, cell survival. We have previously shown that despite expression all isoforms mouse epidermis, PKD1 plays unique critical role wound healing, phorbol ester-induced hyperplasia, tumor development. In translating our findings to human, we discovered not expressed human keratinocytes (KCs) there divergence function other isoforms. Contrary KCs, treatment cultured KCs with pharmacological inhibitors PKDs resulted growth arrest. found PKD2 PKD3 are differentially proliferating differentiating former uniformly present both compartments whereas latter predominantly compartment. Knockdown individual revealed contrasting regulatory roles for PKD3. Loss enhanced KC proliferative potential while loss progressive proliferation defect, clonogenicity diminished tissue regenerative ability. This defect was correlated up-regulation CDK4/6 inhibitor p15INK4B induction p53-independent G1 cycle Simultaneous silencing more pronounced consistent predominant KCs. These data underline importance complexity signaling epidermis suggest central maintaining epidermal homeostasis.