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Cited by 58PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingCytokine Signaling Pathways and Interactions

In brain, Axl recruits Grb2 and the p85 regulatory subunit of PI3 kinase; in vitro mutagenesis defines the requisite binding sites for downstream Akt activation

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Weinger, Jason G., Gohari, Pouyan, Yan, Ying, Backer, Jonathan M., Varnum, Brian, Shafit‐Zagardo, Bridget·2008·Journal of Neurochemistry
DOI 10.1111/j.1471-4159.2008.05343.xPMC PMC2905062
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Abstract

Axl is a receptor tyrosine kinase implicated in cell survival following growth factor withdrawal and other stressors. The binding of Axl’s ligand, growth arrest‐specific protein 6 (Gas6), results in Axl autophosphorylation, recruitment of signaling molecules, and activation of downstream survival pathways. Pull‐down assays and immunoprecipitations using wildtype and mutant Axl transfected cells determined that Axl directly binds growth factor receptor‐bound protein 2 (Grb2) at pYVN and the p85 subunit of phosphatidylinositol‐3 kinase (PI3 kinase) at two pYXXM sites (pY779 and pY821). Also, p85 can indirectly bind to Axl via an interaction between p85’s second proline‐rich region and the N‐terminal SH3 domain of Grb2. Further, Grb2 and p85 can compete for binding at the pY821VNM site. Gas6‐stimulation of Axl‐transfected COS7 cells recruited activated PI3 kinase and phosphorylated Akt. An interaction between Axl, p85 and Grb2 was confirmed in brain homogenates, enriched populations of O4+ oligodendrocytes, and O4− flow‐through prepared from day 10 mouse brain, indicating that cells with active Gas6/Axl signal through Grb2 and the PI3 kinase/Akt pathways.

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  • TAM receptor signaling leads to activation of NF-kB, which is thought to promote cell survival in fibroblasts and endothelial cells.

    “This also leads to activation of NF-kB, which is thought to promote cell survival in fibroblasts and endothelial cells [147, 151, 152].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [147]

    The Discussion (page unavailable) says Gas6/Axl signaling inhibits NF-κB-dependent transcription, contrary to the attributed activation. It discusses survival signaling through PI3 kinase/Akt, but does not link NF-κB activation to survival in fibroblasts or endothelial cells. (LLM, conf=0.88)

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  • Activation of the tyrosine kinase of TAM receptors upon ligand binding recruits the p85 subunit of PI3K and activates PI3K/Akt signaling.

    “Activation of the tyrosine kinase of TAM receptors upon ligand binding recruits the p85 subunit of PI3K and activates PI3K/Akt signaling [147–150].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [147]

    The Discussion (page unavailable in our copy) states that Gas6 stimulation of Axl recruits p85 and active PI3 kinase, leading to Akt activation. The cited study establishes this pathway for Axl, but does not establish p85 recruitment and PI3K/Akt activation for TAM receptors generally, including Tyro3 and Mer. (LLM, conf=0.88)

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Authors
Weinger, J. G., Gohari, P., Yan, Y., Backer, J. M., Varnum, B., & Shafit‐Zagardo, B.
Affiliations
  • Albert Einstein College of Medicine (US)
  • Amgen (United States) (US)
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2008-03-13
Volume
106
Issue
1
Pages
134-146
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/j.1471-4159.2008.05343.x
PMC
PMC2905062
OpenAlex
W2086300703
Cited by
58
References
0
Citations by year
2026: 4 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 2 · 2012: 2
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Amgen
  • National Institutes of Health
  • National Institute of General Medical Sciences (GM-55692, GM 07491, R01GM055692, T32GM007491)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
AXL receptor tyrosine kinase, Grb2, Gas6, Akt activation, SH3 domain binding, oligodendrocytes, brain, cell survival signaling, receptor autophosphorylation
MeSH terms
Axl Receptor Tyrosine Kinase, Animals, Binding Sites, Binding, Competitive, Brain, Chlorocebus aethiops, Enzyme Activation, Humans, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Signal Transduction, Oncogene Proteins, Mutagenesis, Site-Directed, Protein Structure, Tertiary, COS Cells, Phosphatidylinositol 3-Kinases, Receptor Protein-Tyrosine Kinases, Protein Subunits, Proto-Oncogene Proteins c-akt, Mice, GRB2 Adaptor Protein

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