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Vol. 17, Issue 4, 1834-1844, April 2006

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GSK-3 Is Activated by the Tyrosine Kinase Pyk2 during LPA₁-mediated Neurite Retraction

Division of Cellular Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

Submitted July 28, 2005; Revised January 18, 2006; Accepted January 24, 2006
Monitoring Editor: Carl-Henrik Heldin

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase that is usually inactivated by serine phosphorylation in response to extracellular cues. However, GSK-3 can also be activated by tyrosine phosphorylation, but little is known about the upstream signaling events and tyrosine kinase(s) involved. Here we describe a G protein signaling pathway leading to GSK-3 activation during lysophosphatidic acid (LPA)-induced neurite retraction. Using neuronal cells expressing the LPA₁ receptor, we show that LPA₁ mediates tyrosine phosphorylation and activation of GSK-3 with subsequent phosphorylation of the microtubule-associated protein tau via the G_i-linked PIP₂ hydrolysis-Ca²⁺ mobilization pathway. LPA concomitantly activates the Ca²⁺-dependent tyrosine kinase Pyk2, which is detected in a complex with GSK-3. Inactivation or knockdown of Pyk2 inhibits LPA-induced (but not basal) tyrosine phosphorylation of GSK-3 and partially inhibits LPA-induced neurite retraction, similar to what is observed following GSK-3 inhibition. Thus, Pyk2 mediates LPA₁-induced activation of GSK-3 and subsequent phosphorylation of microtubule-associated proteins. Pyk2-mediated GSK-3 activation is initiated by PIP₂ hydrolysis and may serve to destabilize microtubules during actomyosin-driven neurite retraction.

Abbreviations used: GSK-3, glycogen synthase kinase-3; LPA, lysophosphatidic acid; Pyk2, proline-rich tyrosine kinase 2.

^* Present address: Department of Cell Biology and Genetics, Erasmus University, 3000 DR Rotterdam, The Netherlands.

Address correspondence to: C. Laura Sayas (c.sayascasanova{at}erasmusmc.nl).

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