GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-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 LPA(1) receptor, we show that LPA(1) mediates tyrosine phosphorylation and activation of GSK-3 with subsequent phosphorylation of the microtubule-associated protein tau via the G(i)-linked PIP(2) hydrolysis-Ca(2+) mobilization pathway. LPA concomitantly activates the Ca(2+)-dependent tyrosine kinase Pyk2, which is detected in a complex with GSK-3beta. 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 LPA(1)-induced activation of GSK-3 and subsequent phosphorylation of microtubule-associated proteins. Pyk2-mediated GSK-3 activation is initiated by PIP(2) hydrolysis and may serve to destabilize microtubules during actomyosin-driven neurite retraction.
Sayas
C Laura
CL
Division of Cellular Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. c.sayascasanova@erasmusmc.nl
Ariaens
Aafke
A
Ponsioen
Bas
B
Moolenaar
Wouter H
WH
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006868:Hydrolysis; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D016501:Neurites / Q000201:enzymology / Q000502:physiology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D008246:Lysophospholipids; D019269:Phosphatidylinositol 4,5-Diphosphate; D049368:Receptors, Lysophosphatidic Acid; D016875:tau Proteins; D014443:Tyrosine; D051418:Focal Adhesion Kinase 2; D038362:Glycogen Synthase Kinase 3; C032881:lysophosphatidic acid; D002118:Calcium