The MAGUK-family protein CASK is targeted to nuclei of the basal epidermis and controls keratinocyte proliferation
- 15 August 2008
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 121 (16), 2705-2717
- https://doi.org/10.1242/jcs.025643
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 TGFα, 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.Keywords
This publication has 48 references indexed in Scilit:
- Reduced migration, altered matrix and enhanced TGFβ1 signaling are signatures of mouse keratinocytes lacking Sdc1Journal of Cell Science, 2007
- Deletion of CASK in mice is lethal and impairs synaptic functionProceedings of the National Academy of Sciences, 2007
- Nucleoplasmic LAP2α–lamin A complexes are required to maintain a proliferative state in human fibroblastsThe Journal of cell biology, 2007
- Periplakin-dependent re-organisation of keratin cytoskeleton and loss of collective migration in keratin-8-downregulated epithelial sheetsJournal of Cell Science, 2006
- Canonical notch signaling functions as a commitment switch in the epidermal lineageGenes & Development, 2006
- CASK localizes to nuclei in developing skeletal muscle and motor neuron culture models and is agrin‐independentJournal of Cellular Physiology, 2005
- Endogenous Myc controls mammalian epidermal cell size, hyperproliferation, endoreplication and stem cell amplificationJournal of Cell Science, 2005
- A Novel and Conserved Protein-Protein Interaction Domain of Mammalian Lin-2/CASK Binds and Recruits SAP97 to the Lateral Surface of EpitheliaMolecular and Cellular Biology, 2002
- In VitroCharacterization of an Artificial Dermal ScaffoldTissue Engineering, 2001
- Association of Junctional Adhesion Molecule with Calcium/calmodulin-dependent Serine Protein Kinase (CASK/LIN-2) in Human Epithelial Caco-2 CellsPublished by Elsevier BV ,2001