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Novel roles of phosphoinositides in signaling, lipid transport, and disease

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Hammond, Gerald R.V., Burke, John E.·2020·Current Opinion in Cell Biology
DOI 10.1016/j.ceb.2019.12.007PMC PMC7247936
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Abstract

Phosphoinositides (PPIns) are lipid signaling molecules that act as master regulators of cellular signaling. Recent studies have revealed novel roles of PPIns in myriad cellular processes and multiple human diseases mediated by misregulation of PPIn signaling. This review will present a timely summary of recent discoveries in PPIn biology, specifically their role in regulating unexpected signaling pathways, modification of signaling outcomes downstream of integral membrane proteins, and novel roles in lipid transport. This has revealed new roles of PPIns in regulating membrane trafficking, immunity, cell polarity, and response to extracellular signals. A specific focus will be on novel opportunities to target PPIn metabolism for treatment of human diseases, including cancer, pathogen infection, developmental disorders, and immune disorders.

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Crossref · 10.1016/j.ceb.2019.12.007

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  • PI(4,5)P2 is a substrate for PLC and PI3K.

    “PI(4,5)P2 is a substrate for two signalling pathways.”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [15]

    The Introduction’s lipid-transfer-proteins section says PI(4,5)P2 is presented to PLCβ3 for hydrolysis, supporting the PLC part. The passages on PI3K discuss its role in disease but do not say that PI(4,5)P2 is its substrate, so the second pathway is not established by our copy. No page numbers are provided. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PLC hydrolysis of PI(4,5)P2 generates IP3 and DAG.

    “Phospholipase C (PLC) leads to the generation of two second messengers, inositol(1,4,5)trisphosphate (I(1,4,5)P3), known trigger for mobilising Ca2+ from endoplasmic reticulum (ER) stores and diacylglycerol (DAG), an activator for protein kinase C (PKC).”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [15]

    The Introduction’s lipid-transfer-proteins section says that PLCβ3 hydrolyzes PI(4,5)P2, supporting the substrate-and-enzyme part of the claim. Our copy does not state that this produces IP3 and DAG, or describe the cited sentence’s downstream calcium and PKC effects; the relevant passages have no page numbers. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • PI3K generates PI(3,4,5)P3, a lipid with wide-ranging functions.

    “The second pathway is phosphoinositide-3-kinase (PI3K) to make PI(3,4,5)P3, a lipid with wide-ranging functions.”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [15]

    The Introduction’s section on pathological phosphoinositide metabolism describes PI3K signaling in cancer, immunodeficiencies, growth disorders, and insulin signaling, supporting the broad point that the pathway has wide-ranging roles. However, the passages in our copy do not state that PI3K generates PI(3,4,5)P3 or specifically attribute those functions to that lipid (page unavailable). (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • PIP2 plays a crucial role in regulating actin polymerisation, endocytosis, exocytosis, ion channels and G-protein-coupled receptors.

    “PIP2 plays a crucial role in regulating a number of cellular processes or molecules, including actin polymerisation, endocytosis, exocytosis, ion channels and G-protein-coupled receptors [78, 79].”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [78]

    The Introduction section on integral membrane protein signaling identifies PI(4,5)P2 as a key regulator of ion-channel opening and describes its effects on GPCR signaling. It also says GPCR endocytosis is proposed to require phosphoinositide binding, but does not specifically establish a PIP2 role there. Searches of our copy for actin and exocytosis found no support for those parts of the list; page numbers were not available in the indexed passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • IP3 mobilises Ca2+ from ER stores.

    “Phospholipase C (PLC) leads to the generation of two second messengers, inositol(1,4,5)trisphosphate (I(1,4,5)P3), known trigger for mobilising Ca2+ from endoplasmic reticulum (ER) stores and diacylglycerol (DAG), an activator for protein kinase C (PKC).”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [15]

    The Introduction section on integral membrane protein signaling says that GPCRs activate PLC and deplete PI(4,5)P2, but it does not say that IP3 mobilizes Ca2+ from ER stores. Searches for IP3, inositol trisphosphate, and ER calcium release found no passage addressing that claim in our copy. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 86

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Cited by

Sorted by citations

Authors
Hammond, G. R. V., & Burke, J. E.
Affiliations
  • University of Pittsburgh (US)
  • University of Victoria (CA)
Corresponding author
  • Hammond, Gerald R.V.
  • Burke, John E.
ORCID
Venue
Current Opinion in Cell Biology
Publisher
Elsevier BV
Published
2020-04
Volume
63
Pages
57-67
ISSN
0955-0674 (ISSN-L)
DOI
10.1016/j.ceb.2019.12.007
PMC
PMC7247936
OpenAlex
W3001602420
Cited by
203
References
6
Citations by year
2026: 22 · 2025: 39 · 2024: 38 · 2023: 37 · 2022: 34 · 2021: 19 · 2020: 12 · 2019: 2
FWCI
2.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (1R35GM119412-01)
  • Natural Sciences and Engineering Research Council of Canada (2014-05218)
  • Canadian Institutes of Health Research (CRN-142393)
  • Michael Smith Foundation for Health Research (17686)
  • Cancer Research Society (CRS 24368)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
phosphoinositides, lipid signaling, lipid transport, membrane trafficking, cell polarity, immunity, cancer, pathogen infection, developmental disorders, immune disorders, therapeutic target
MeSH terms
Biological Transport, Humans, Phosphatidylinositols, Signal Transduction

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