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Dysfunction of phospholipase Cγ in immune disorders and cancer
Abstract
The surge in genetic and genomic investigations over the past 5 years has resulted in many discoveries of causative variants relevant to disease pathophysiology. Although phospholipase C (PLC) enzymes have long been recognized as important components in intracellular signal transmission, it is only recently that this approach highlighted their role in disease development through gain-of-function mutations. In this review we describe the new findings that link the PLCγ family to immune disorders and cancer, and illustrate further efforts to elucidate the molecular mechanisms that underpin their dysfunction.
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“The protective variant P522R is certainly located within a region of the enzyme that has a regulatory function (Fig. 4d, [7])”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [7]
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“Although not covered in this review, the importance of aberrant functions of different PLCs and PI3Ks in disease development is well established and continues to expand [11,62,67,72,134–138].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [137]
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“A main effector downstream of TREM2, PLCγ2 is an intracellular lipase recruited to the membrane upon activation [3, 4].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [3]
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“the majority of hypermorphic variants (S707Y, Y495C, D993G) have been identified in the context of APLAID disorders, and in some mouse models with autoinflammatory phenotypes [3, 109, 110]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [3]
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“PLCγ2 is present in circulating monocytes, platelets and B-cells, amongst other immune cells (see sections above, [3, 130])”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [3]
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“PLCγ2 shares high structural and mechanistic overlap with the other member of the PLCγ family, PLCγ1 [7].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [7]
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“Other mutations in PLCG2 that lead to immune dysfunction are known to be activating [7].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [7]
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“While PLCγ1 is ubiquitously expressed and regulates growth factor signalling in a variety of cell types, expression of PLCγ2 is largely restricted to hematopoietic cells, and regulates specific responses downstream of several immune receptors8.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [8]
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“with variants of these genes known to cause diseases such as Nasu-Hakola disease (TREM2) [22], and PLCγ2-associated antibody deficiency (PLAID), or autoinflammation and PLAID (APLAID) [3].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [3]
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“PLAID-affected individuals have reduced PLCγ2-mediated signal transduction at physiological temperatures, despite constitutive enzyme activation [3, 113]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [3]
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Cites
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Self-citationCold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions
Ombrello, M. J., Remmers, E. F., Sun, G., Freeman, A. F., Datta, S., Torabi-Parizi, P., Subramanian, N., Bunney, T. D., Baxendale, R. W., Martins, M. S., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1102140 · Cited by 425
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Metadata
- Authors
- Koss, H., Bunney, T. D., Behjati, S., & Katan, M.
- Affiliations
- Institute of Structural and Molecular Biology (GB)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Bunney, Tom D.
- Katan, Matilda
- Venue
- Trends in Biochemical Sciences
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 39
- Issue
- 12
- Pages
- 603-611
- ISSN
- 0968-0004 (ISSN-L)
- OpenAlex
- W2090368019
- Cited by
- 115
- References
- 57
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 6 · 2023: 17 · 2022: 14 · 2021: 13 · 2020: 20 · 2019: 12 · 2018: 5 · 2017: 6 · 2016: 6 · 2015: 8
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Biochemical Sciences (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK (16567)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- phospholipase C-gamma, immune disorders, cancer, gain-of-function mutations, intracellular signaling, disease pathophysiology, genetic variants
- MeSH terms
- Animals, Diglycerides, Humans, Immune System Diseases, Models, Biological, Models, Molecular, Mutation, Neoplasms, Protein Conformation, Second Messenger Systems, Inositol 1,4,5-Trisphosphate, Phospholipase C gamma
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