GSKIP, an Inhibitor of GSK3β, Mediates the N-Cadherin/β-Catenin Pool in the Differentiation of SH-SY5Y Cells

Emerging evidence has shown that GSK3 beta plays a pivotal role in regulating the specification of axons and dendrites. Our previous study has shown a novel GSK3 beta interaction protein (GSKIP) able to negatively regulate GSK3 beta in Writ signaling pathway. To further characterize how GSKIP functions in neurons, human neuroblastoma SH-SY5Y cells treated with retinoic acid (RA) to differentiate to neuron-like cells was used as a model. Overexpression of GSKIP prevents neurite outgrowth in SH-SY5Y cells. GSKIP may affect GSK3 beta activity on neurite outgrowth by inhibiting the specific phosphorylation of tau (ser396). GSKIP also increases beta-catenin in the nucleus and raises the level of cyclin D1 to promote cell-cycle progression in SH-SY5Y cells. Additionally, overexpression of GSKIP downregulates N-cadherin expression, resulting in decreased recruitment of beta-catenin. Moreover, depletion of beta-catenin by small interfering RNA, neurite outgrowth is blocked in SH-SY5Y cells. Altogether, we propose a model to show that GSKIP regulates the functional interplay of the GSK3 beta/beta-catenin, beta-catenin/cyclin D1, and beta-catenin/N-cadherin pool during RA signaling in SH-SY5Y cells. J. Cell. Biochem. 108: 1325-1336, 2009. (C) 2009 Wiley-Liss, Inc.