Phosphoinositide signalling in cancer: beyond PI3K and PTEN
Abstract
There are numerous studies that suggest multiple links between the cellular phosphoinositide system and cancer. As key roles in cancer have been established for PI3K and PTEN - enzymes that regulate the levels of phosphatidylinositol-3,4,5-trisphosphate - compounds targeting this pathway are entering the clinic at a rapid pace. Several other phosphoinositide-modifying enzymes, including phosphoinositide kinases, phosphatases and phospholipase C enzymes, have been implicated in the generation and progression of tumours. Studies of these enzymes are providing new insights into the mechanisms and the extent of their involvement in cancer, highlighting new potential targets for therapeutic intervention.
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PLCG2 mediates the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
“PLCG2 associates with the membrane and mediates the hydrolysis of phosphatidylinositol 4, 5‐bisphosphate (PIP2) into two important second messengers: inositol 1, 4, 5‐trisphosphate (IP3) and diacylglycerol (DAG). 14 , 15”
From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [15]
PLCG1 is ubiquitously distributed, and its mutations are associated with some cancers and neuropsychiatric disorders.
“PLCG1 is ubiquitously distributed, and mutations are associated with some forms of cancers, such as cutaneous T cell lymphoma [8, 9], but also neuropsychiatric disorders [10].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [8]
Upon activation, PLCγ2 hydrolyses the PM-inner-leaflet-localised lipid, PIP2, to produce inositol (1,4,5)-trisphosphate and diacylglycerol (DAG).
“Upon activation, PLCγ2 hydrolyses the PM-inner-leaflet-localised lipid, PIP2, to produce inositol (1,4,5)-trisphosphate and diacylglycerol (DAG) [75, 76].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [75]
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Oncogenic Roles of the PI3K/AKT/mTOR axis
Aoki, M., & Fujishita, T. (2017) · Current topics in microbiology and immunology · doi:10.1007/82_2017_6 · Cited by 355 · see citing works
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Magno, L., Lessard, C. B., Martins, M., Lang, V., Cruz, P., Asi, Y., Katan, M., Bilsland, J., Lashley, T., Chakrabarty, P., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0469-0 · Cited by 143 · see citing works
Self-citationThe regulation of cancer cell death and metabolism by extracellular matrix attachment
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Self-citationMagno, L., Bunney, T. D., Mead, E., Svensson, F., & Bictash, M. N. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00436-5 · Cited by 64 · see citing works
Self-citationPhosphatidylserine synthesis controls oncogenic B cell receptor signaling in B cell lymphoma
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Bedford, L. M., Tutrow, K. D., Hooper, K., Messenger, E. J., Hernandez, M., Lamb, B. T., Meyer, J. S., Richardson, T. I., & Bissel, S. J. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70772 · Cited by 8 · see citing works
“14,15 IP3 triggers calcium release from intracellular stores, while DAG activates protein kinase C (PKC) and other effector proteins, ultimately influencing microglial processes such as migration, phagocytosis, cytokine secretion, and metabolic responses.”
- Authors
- Bunney, T. D., & Katan, M.
- Affiliations
- Institute of Cancer Research (GB)
- Corresponding author
- Katan, Matilda
- Venue
- Nature Reviews Cancer
- Published
- 2010-05
- Volume
- 10
- Issue
- 5
- Pages
- 342-352
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2009826571
- Cited by
- 400
- References
- 4
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 15 · 2023: 17 · 2022: 15 · 2021: 19 · 2020: 20 · 2019: 22 · 2018: 17 · 2017: 30 · 2016: 30 · 2015: 28 · 2014: 30 · 2013: 38 · 2012: 39
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- phosphoinositide signaling, cancer, phosphatidylinositol 3-kinase, PTEN, phosphatidylinositol 3,4,5-trisphosphate, phosphoinositide kinases, phosphoinositide phosphatase, phospholipase C, tumor progression, therapeutic target
- MeSH terms
- Animals, Antineoplastic Agents, Enzyme Inhibitors, Humans, Neoplasms, Signal Transduction, Phosphatidylinositol 3-Kinases, PTEN Phosphohydrolase
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