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Cited by 341PI3K/AKT/mTOR signaling in cancerProtein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase Signaling

SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival

Open access
Liu, Q., Sasaki, T., Kozieradzki, I., Wakeham, A., Itie, A., Dumont, D. J., Penninger, J. M.·1999·Genes & Development
DOI 10.1101/gad.13.7.786PMC PMC316591
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Abstract

SHIP is an inositol 5' phosphatase that hydrolyzes the PI3'K product PI(3,4,5)P3. We show that SHIP-deficient mice exhibit dramatic chronic hyperplasia of myeloid cells resulting in splenomegaly, lymphadenopathy, and myeloid infiltration of vital organs. Neutrophils and bone marrow-derived mast cells from SHIP-/- mice are less susceptible to programmed cell death induced by various apoptotic stimuli or by growth factor withdrawal. Engagement of IL3-R and GM-CSF-R in these cells leads to increased and prolonged PI3'K-dependent PI(3,4,5)P3 accumulation and PKB activation. These data indicate that SHIP is a negative regulator of growth factor-mediated PKB activation and myeloid cell survival.

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  • Conditional Inpp5d knockdown in microglia avoids the developmental effects that can occur in constitutive knockouts.

    “This strategy also avoids the developmental effects that can occur in constitutive knockouts.16,17”

    From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [16]

    The 'Generation of SHIP-deficient mice' section reports that mice lacking SHIP from birth had enlarged spleens apparent by four weeks and progressive abnormalities in myeloid cells. This supports concern about effects of a constitutive knockout, but the paper does not examine conditional Inpp5d knockdown in microglia or show that it avoids developmental effects. Page numbers were not available in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Microglial activation and actin remodeling are processes that can be mediated by Inpp5d.

    “which are both processes that can be mediated by Inpp5d. 6 , 20”

    From Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [6]

    The paper’s Abstract (page unavailable) says PI3K and phospholipid-regulated signaling are implicated in cytoskeletal reorganization, and the SHIP-regulates-PKB section describes SHIP’s role in that signaling pathway. This provides indirect support for a connection to actin remodeling, but the paper does not show SHIP mediating actin remodeling or address microglial activation. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • Upon binding to PI(3,4,5)P3, the 5' phosphatase catalytic domain phosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, which can bind to the C2 domain near the C-terminus.

    “Upon binding to PI(3,4,5)P3, the 5’ phosphatase catalytic domain phosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, which can bind to the C2 domain near the C-terminus [92, 107, 108].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [92]

    The passage labeled Abstract (page unavailable) says SHIP hydrolyzes PI(3,4,5)P3 to generate PI(3,4)P2. It does not say the phosphatase phosphorylates PI(3,4,5)P3, and the passages do not support the claimed binding of PI(3,4)P2 to a C-terminal C2 domain. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • SHIP1 is a phosphatase involved in phosphoinositide signaling.

    “SHIP1 is a phosphatase involved in phosphoinositide signaling.”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [92]

  • PI(3,4,5)P3 can be converted back to PI(4,5)P2 by PTEN or converted into PI(3,4)P2 by SHIP1, which negatively regulates PI3K/Akt signaling.

    “PI(3,4,5)P3 can be converted back to PI(4,5)P2 by the protein phosphatase and tensin homology (PTEN) or converted into PI(3,4)P2 by SHIP1, which negatively regulates PI3K/Akt signaling (Fig. 2) [89–92].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [92]

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Authors
Liu, Q., Sasaki, T., Kozieradzki, I., Wakeham, A., Itie, A., Dumont, D. J., & Penninger, J. M.
Affiliations
University of Toronto (CA)
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
1999-04-01
Volume
13
Issue
7
Pages
786-791
ISSN
0890-9369 (ISSN-L)
DOI
10.1101/gad.13.7.786
PMC
PMC316591
OpenAlex
W2151313755
Cited by
341
References
31
Citations by year
2026: 1 · 2025: 4 · 2024: 7 · 2023: 12 · 2022: 5 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 10 · 2017: 8 · 2016: 9 · 2015: 7 · 2014: 10 · 2013: 14 · 2012: 17
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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 Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
ships, inositol polyphosphate 5-phosphatase, phosphatidylinositol 3-kinase, phosphatidylinositol 3,4,5-trisphosphate, Akt signaling, apoptosis, GM-CSF receptor, growth factor withdrawal, myeloid hyperplasia, splenomegaly, mast cells, neutrophils
MeSH terms
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, Anisomycin, Bone Marrow, Cell Line, Cell Survival, Cycloheximide, Enzyme Activation, Interleukin-3, Mice, Inbred C57BL, Neutrophils, Phosphoric Monoester Hydrolases, Precipitin Tests, Proto-Oncogene Proteins, Sorbitol, Spleen, Time Factors, Blotting, Southern, Blotting, Western, Down-Regulation, Apoptosis, Protein Serine-Threonine Kinases, Mice, Knockout, Proto-Oncogene Proteins c-akt, Mice

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