GSK-3 Is Activated by the Tyrosine Kinase Pyk2 during LPA1-mediated Neurite Retraction
Open accessAbstract
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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Pyk2 mediates GSK-3 activation and subsequent Tau phosphorylation.
“Pyk2 has been reported to mediate GSK-3 activation and subsequent Tau phosphorylation [112].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [112]
Cerebral GSK3β stimulation by phosphorylation at Y216 is mediated by intracellular calcium levels and calcium-dependent PYK2.
“Cerebral GSK3β stimulation by phosphorylation at Y216 is mediated by intracellular calcium levels and calcium-dependent PYK2 (Hartigan and Johnson, 1999; Hartigan et al., 2001; Sayas et al., 2006).”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Sayas et al., 2006
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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
- PMC
- PMC1415316
- 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
- green
- europepmc.org
- 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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