GSK-3 is activated by the tyrosine kinase Pyk2 during LPA 1-mediated neurite retraction

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 Gi-linked PIP2 hydrolysis-Ca2+ mobilization pathway. LPA concomitantly activates the Ca2+-dependent tyrosine kinase Pyk2, which is detected in a complex with GSK-3β. 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 LPAi-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.

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