Cited by 115Protein Kinase Regulation and GTPase SignalingSphingolipid Metabolism and SignalingWnt/β-catenin signaling in development and cancer

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

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Sayas, C. Laura, Ariaens, Aafke, Ponsioen, Bas, Moolenaar, Wouter H.·2006·Molecular Biology of the Cell

Abstract

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-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 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.

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Crossref · 10.1091/mbc.e05-07-0688

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Authors
Sayas, C. L., Ariaens, A., Ponsioen, B., & Moolenaar, W. H.
Affiliations
The Netherlands Cancer Institute (NL)
Venue
Molecular Biology of the Cell
Published
2006-04
Volume
17
Issue
4
Pages
1834-1844
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
OpenAlex
W2131438817
Cited by
115
References
74
Citations by year
2026: 5 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 8 · 2013: 9 · 2012: 6
FWCI
2.45
Type
journal article
Language
en
Open access
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
KWF Kankerbestrijding
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
glycogen synthase kinase-3, Pyk2, lysophosphatidic acid, LPA1 receptor, neurite retraction, tyrosine phosphorylation, G protein signaling, PIP2 hydrolysis, calcium mobilization, tau phosphorylation, microtubule destabilization, actomyosin, GSK3β
MeSH terms
Animals, Calcium, Enzyme Activation, Hydrolysis, Lysophospholipids, Phosphorylation, Tyrosine, Neurites, tau Proteins, Phosphatidylinositol 4,5-Diphosphate, Glycogen Synthase Kinase 3, Receptors, Lysophosphatidic Acid, Mice, Rats, Focal Adhesion Kinase 2

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