The MAGUK-family protein CASK is targeted to nuclei of the basal epidermis and controls keratinocyte proliferation

Abstract

The Ca2+/calmodulin-associated Ser/Thr kinase (CASK) binds syndecans and other cell-surface proteins through its PDZ domain and has been implicated in synaptic assembly, epithelial polarity and neuronal gene transcription. We show here that CASK regulates proliferation and adhesion of epidermal keratinocytes. CASK is localised in nuclei of basal keratinocytes in newborn rodent skin and developing hair follicles. Induction of differentiation shifts CASK to the cell membrane, whereas in keratinocytes that have been re-stimulated after serum starvation CASK localisation shifts away from membranes upon entry to S phase. Biochemical fractionation demonstrates that CASK has several subnuclear targets and is found in both nucleoplasmic and nucleoskeletal pools. Knockdown of CASK by RNA interference leads to increased proliferation in cultured keratinocytes and in organotypic skin raft cultures. Accelerated cell cycling in CASK knockdown cells is associated with upregulation of Myc and hyperphosphorylation of Rb. Moreover, CASK-knockdown cells show increased hyperproliferative response to KGF and TGFalpha, and accelerated attachment and spreading to the collagenous matrix. These functions are reflected in wound healing, where CASK is downregulated in migrating and proliferating wound-edge keratinocytes.