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Cited by 42Protein Tyrosine PhosphatasesPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

Targeting SHIP1 and SHIP2 in Cancer

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Pedicone, Chiara, Meyer, Shea T., Chisholm, John D., Kerr, William G.·2021·Cancers
DOI 10.3390/cancers13040890PMC PMC7924360
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Abstract

Membrane-anchored and soluble inositol phospholipid species are critical mediators of intracellular cell signaling cascades. Alterations in their normal production or degradation are implicated in the pathology of a number of disorders including cancer and pro-inflammatory conditions. The SH2-containing 5′ inositol phosphatases, SHIP1 and SHIP2, play a fundamental role in these processes by depleting PI(3,4,5)P3, but also by producing PI(3,4)P2 at the inner leaflet of the plasma membrane. With the intent of targeting SHIP1 or SHIP2 selectively, or both paralogs simultaneously, small molecule inhibitors and agonists have been developed and tested in vitro and in vivo over the last decade in various disease models. These studies have shown promising results in various pre-clinical models of disease including cancer and tumor immunotherapy. In this review the potential use of SHIP inhibitors in cancer is discussed with particular attention to the molecular structure, binding site and efficacy of these SHIP inhibitors.

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  • 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 [108]

    Section 7 says the SHIP phosphatase hydrolyzes the 5′ phosphate of PI(3,4,5)P3 to produce PI(3,4)P2; it does not phosphorylate the substrate. Section 6 supports the separate point that PI(3,4)P2 can bind the C2 domain. Page numbers were not available in our copy. (LLM, conf=0.90)

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  • SHIP1 binds to PI(3,4,5)P3 via its PH-L domain and dephosphorylates PI(3,4,5)P3 via its 5' phosphatase catalytic domain to generate PI(4,5)P2.

    “SHIP1 binds to PI(3,4,5)P3 via its PH-L domain and dephosphorylates PI(3,4,5)P3 via its 5’ phosphatase catalytic domain to generate PI(4,5)P2.”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [108]

    Section 3 explicitly distinguishes the products: SHIP converts PI(3,4,5)P3 to PI(3,4)P2, while PTEN produces PI(4,5)P2. Section 7 also identifies PI(3,4)P2 as the product of SHIP’s 5′-phosphate hydrolysis. The claimed product is therefore contrary to the source; the cited passages do not establish binding via a PH-L domain. Page numbers were not available in our copy. (LLM, conf=0.94)

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  • C2 domain of SHIP1 can bind to PI(4,5)P2, which is thought to allosterically regulate SHIP1's phosphatase activity.

    “C2 domain of SHIP1 can bind to PI(4,5)P2, which is thought to allosterically regulate SHIP1’s phosphatase activity.”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [108]

    Section 6 (page unavailable) identifies PI(3,4)P2—not the claimed PI(4,5)P2—as binding to the SHIP1 C2 domain and accelerating its phosphatase reaction. The paper discusses possible allosteric acceleration, but for the different lipid named in the passage. (LLM, conf=0.87)

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References 190 · Cited by 42

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Authors
Pedicone, C., Meyer, S. T., Chisholm, J. D., & Kerr, W. G.
Affiliations
  • SUNY Upstate Medical University (US)
  • Syracuse University (US)
Corresponding author
Kerr, William G.
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2021-02-20
Volume
13
Issue
4
Pages
890
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers13040890
PMC
PMC7924360
OpenAlex
W3130174364
Cited by
42
References
190
Citations by year
2026: 8 · 2025: 8 · 2024: 10 · 2023: 6 · 2022: 8 · 2021: 2
FWCI
0.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Institute on Aging (RF1AG059717)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • 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
Keywords
SHIP1, SHIP2, PI(3,4)P2, inositol phospholipids, small molecule inhibitors, cancer, cancer immunotherapy, binding site structure

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