The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi
Raamsdonk, C. D. V., Bezrookove, V., Green, G., Bauer, J. M., Gaugler, L., O’Brien, J. M., Simpson, E. M., Barsh, G. S., & Bastian, B. C. (2008) · Nature · doi:10.1038/nature07586 · Cited by 1,648
Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation
Balla, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00028.2012 · Cited by 1,638
Regulation of Phosphoinositide-Specific Phospholipase C
Rhee, S. G. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.281 · Cited by 1,628
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1400029 · Cited by 1,275
Initial impact of the sequencing of the human genome
Lander, E. S. (2011) · Nature · doi:10.1038/nature09792 · Cited by 1,044
Structure, Function, and Control of Phosphoinositide-Specific Phospholipase C
Rebecchi, M. J., & Pentyala, S. (2000) · Physiological Reviews · doi:10.1152/physrev.2000.80.4.1291 · Cited by 1,000
Kim, H.-K., Kim, J., Zilberstein, A., Margolis, B. L., Kim, J. G., Schlessinger, J., & Rhee, S. G. (1991) · Cell · doi:10.1016/0092-8674(91)90461-7 · Cited by 570
Kadamur, G., & Ross, E. M. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183750 · Cited by 529
Multiple roles of phosphoinositide-specific phospholipase C isozymes
Suh, P.-G., Park, J.-I., Manzoli, L., Cocco, L., Peak, J. C., Katan, M., Fukami, K., Kataoka, T., Yun, S.-U., & Ryu, S.-H. (2008) · BMB Reports · doi:10.5483/bmbrep.2008.41.6.415 · Cited by 501
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
Self-citationPhosphoinositide signalling in cancer: beyond PI3K and PTEN
Bunney, T. D., & Katan, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2842 · Cited by 400
Self-citationZhou, Q., Lee, G.-S., Brady, J., Datta, S., Katan, M., Sheikh, A., Martins, M. S., Bunney, T. D., Santich, B. H., Moir, S., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.08.006 · Cited by 374
Self-citationRecurrent PTPRB and PLCG1 mutations in angiosarcoma
Behjati, S., Tarpey, P. S., Sheldon, H., Martincorena, I., Loo, P. V., Gundem, G., Wedge, D. C., Ramakrishna, M., Cooke, S. L., Pillay, N., et al. (2014) · Nature Genetics · doi:10.1038/ng.2921 · Cited by 307
Self-citationPLCG1 mutations in cutaneous T-cell lymphomas
Vaqué, J. P., Gómez-López, G., Monsálvez, V., Varela, I., Martínez, N., Pérez, C., Domínguez, O., Graña, O., Rodríguez-Peralto, J. L., Rodríguez-Pinilla, S. M., et al. (2014) · Blood · doi:10.1182/blood-2013-05-504308 · Cited by 229
The Phospholipase C Isozymes and Their Regulation
Gresset, A., Sondek, J., & Harden, T. K. (2012) · Subcellular Biochemistry · doi:10.1007/978-94-007-3012-0_3 · Cited by 196
PLC regulation: emerging pictures for molecular mechanisms
Bunney, T. D., & Katan, M. (2011) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.08.003 · Cited by 182
Self-citationYu, P., Constien, R., Dear, N., Katan, M., Hanke, P., Bunney, T. D., Kunder, S., Quintanilla-Martinez, L., Huffstadt, U., Schröder, A., et al. (2005) · Immunity · doi:10.1016/j.immuni.2005.01.018 · Cited by 177
Self-citationBae, J. H., Lew, E. D., Yuzawa, S., Tomé, F., Lax, I., & Schlessinger, J. (2009) · Cell · doi:10.1016/j.cell.2009.05.028 · Cited by 158
Structural and Mechanistic Insights into Ras Association Domains of Phospholipase C Epsilon
Bunney, T. D., Harris, R., Gandarillas, N. L., Josephs, M. B., Roe, S. M., Sorli, S., Paterson, H. F., Rodrigues‐Lima, F., Esposito, D., Ponting, C. P., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.008 · Cited by 134
Self-citationHeinz, D. W., Essen, L., & Williams, R. L. (1998) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1490 · Cited by 120
Poulin, B., Sekiya, F., & Rhee, S. G. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409590102 · Cited by 110
Mechanism of Phosphorylation-induced Activation of Phospholipase C-γ Isozymes
Gresset, A., Hicks, S. N., Harden, T. K., & Sondek, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.166512 · Cited by 110
The physiological roles of primary phospholipase C
Yang, Y. R., Follo, M. Y., Cocco, L., & Suh, P. (2013) · Advances in Biological Regulation · doi:10.1016/j.jbior.2013.08.003 · Cited by 104
Fu, L., Qin, Y., Xie, D., Hu, L., Kwong, D. L. �., Srivastava, G., Tsao, S. W., & Guan, X. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2411 · Cited by 90
Bunney, T. D., Esposito, D., Mas-Droux, C., Lamber, E., Baxendale, R. W., Martins, M., Cole, A., Svergun, D., Driscoll, P. C., & Katan, M. (2012) · Structure · doi:10.1016/j.str.2012.09.005 · Cited by 88
Self-citationRole of phospholipase C in cell invasion and metastasis
Lattanzio, R., Piantelli, M., & Falasca, M. (2013) · Advances in Biological Regulation · doi:10.1016/j.jbior.2013.07.006 · Cited by 84
Isozyme-specific stimulation of phospholipase C-γ2 by Rac GTPases
Piechulek, T., Rehlen, T., Walliser, C., Vatter, P., Moepps, B., & Gierschik, P. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509396200 · Cited by 80
Direct Activation of Human Phospholipase C by Its Well Known Inhibitor U73122
Klein, R. R., Bourdon, D., Costales, C., Wagner, C. D., White, W. L., Williams, J. D., Hicks, S. N., Sondek, J., & Thakker, D. R. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.191783 · Cited by 78
Mechanism of Activation and Inactivation of Gq/Phospholipase C-β Signaling Nodes
Harden, T. K., Waldo, G. L., Hicks, S. N., & Sondek, J. (2011) · Chemical Reviews · doi:10.1021/cr200209p · Cited by 75
Hu, X., Zhang, F. B., Fan, Y. C., Shu, X. S., Wong, A., Zhou, W., Shi, Q. L., Tang, H. M., Fu, L., Guan, X. Y., et al. (2009) · Oncogene · doi:10.1038/onc.2009.92 · Cited by 73
Bunney, T. D., Opaleye, O., Roe, S. M., Vatter, P., Baxendale, R. W., Walliser, C., Everett, K. L., Josephs, M. B., Christow, C., Rodrigues-Lima, F., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.02.023 · Cited by 72
Self-citationToward the mechanism of phosphoinositide-specific phospholipases C
Bruzik, K. S., & Tsai, M. (1994) · Bioorganic & Medicinal Chemistry · doi:10.1016/s0968-0896(00)82002-7 · Cited by 67
Phospholipase C epsilon plays a suppressive role in incidence of colorectal cancer
Wang, X., Zhou, C., Qiu, G., Yang, Y., Yan, D., Xing, T., Fan, J., Tang, H., & Peng, Z. (2011) · Medical Oncology · doi:10.1007/s12032-011-9981-1 · Cited by 65
Danielsen, S. A., Cekaite, L., Ågesen, T. H., Sveen, A., Nesbakken, A., Thiis‐Evensen, E., Skotheim, R. I., Lind, G. E., & Lothe, R. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024419 · Cited by 64
Characterization of Phospholipase Cγ Enzymes with Gain-of-Function Mutations
Everett, K. L., Bunney, T. D., Yoon, Y., Rodrigues-Lima, F., Harris, R., Driscoll, P. C., Abe, K., Fuchs, H., Hrabé de Angelis, M., Yu, P., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.019265 · Cited by 63
Self-citationThe identification of novel PLC-γ inhibitors using virtual high throughput screening
Reynisson, J., Court, W. J., O’Neill, C., Day, J. E. H., Patterson, L., McDonald, E., Workman, P., Katan, M., & Eccles, S. A. (2009) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2009.02.049 · Cited by 58
Self-citationBerven, L. A., & Barritt, G. J. (1995) · Biochemical Pharmacology · doi:10.1016/0006-2952(95)00050-a · Cited by 58
Tumor suppressor role of phospholipase Cε in Ras-triggered cancers
Martins, M., McCarthy, A., Baxendale, R. W., Guichard, S., Magno, L., Kessaris, N., El-Bahrawy, M. A., Yu, P., & Katan, M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311500111 · Cited by 51
Self-citationAbe, K., Fuchs, H., Boersma, A., Hans, W., Yu, P., Kalaydjiev, S., Klaften, M., Adler, T., Calzada‐Wack, J., Mossbrugger, I., et al. (2011) · Arthritis & Rheumatism · doi:10.1002/art.30280 · Cited by 46
Self-citationEvidence for separate effects of U73122 on phospholipase C and calcium channels in human platelets
Pulcinelli, F. M., Gresele, P., Bonuglia, M., & Gazzaniga, P. P. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(98)00146-4 · Cited by 45
Feißt, C., Albert, D., Steinhilber, D., & Werz, O. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.011007 · Cited by 45
Autoinhibition and Phosphorylation-Induced Activation of Phospholipase C-γ Isozymes
Hajicek, N., Charpentier, T. H., Rush, J. R., Harden, T. K., & Sondek, J. (2013) · Biochemistry · doi:10.1021/bi400433b · Cited by 41
Diverse cellular and physiological roles of phospholipase C-γ1
Yang, Y. R., Choi, J. H., Chang, J., Kwon, H. M., Jang, H., Ryu, S. H., & Suh, P. (2011) · Advances in Biological Regulation · doi:10.1016/j.advenzreg.2011.09.017 · Cited by 39
Small Molecule Inhibitors of Phospholipase C from a Novel High-throughput Screen*
Huang, W., Barrett, M. O., Hajicek, N., Hicks, S. C., Harden, T. K., Sondek, J., & Zhang, Q. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.422501 · Cited by 39
Wang, J. P. (1996) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf00167177 · Cited by 37
Burgdorf, C., Schäfer, U., Richardt, G., & Kurz, T. (2010) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e3181d8bec5 · Cited by 37
Intramolecular Regulation of Phospholipase C-γ1 by Its C-Terminal Src Homology 2 Domain
DeBell, K. E., Graham, L. J., Reischl, I. G., Serrano, C. J., Bonvini, E., & Rellahan, B. L. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01400-06 · Cited by 36
A Fluorogenic, Small Molecule Reporter for Mammalian Phospholipase C Isozymes
Huang, W., Hicks, S. N., Sondek, J., & Zhang, Q. (2010) · ACS Chemical Biology · doi:10.1021/cb100308n · Cited by 33
Strike a pose: Gαq complexes at the membrane
Lyon, A. M., Taylor, V. G., & Tesmer, J. J. G. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.10.008 · Cited by 29
Genetics, genomics, and their relevance to pathology and therapy
Ombrello, M. J., Sikora, K. A., & Kastner, D. L. (2014) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2014.05.001 · Cited by 26
Membrane Environment Exerts an Important Influence on Rac-Mediated Activation of Phospholipase Cγ2
Everett, K. L., Buehler, A., Bunney, T. D., Margineanu, A., Baxendale, R. W., Vatter, P., Retlich, M., Walliser, C., Manning, H. B., Neil, M. A. A., et al. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01408-10 · Cited by 25
Self-citationSynthesis and Evaluation of Fluorogenic Substrates for Phospholipase D and Phospholipase C
Rose, T. M., & Prestwich, G. D. (2006) · Organic Letters · doi:10.1021/ol060773d · Cited by 24
The PI‐PLC inhibitor U‐73122 is a potent inhibitor of the SERCA pump in smooth muscle
Hollywood, M. A., Sergeant, G. P., Thornbury, K. D., & McHale, N. G. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00795.x · Cited by 22
Rukavishnikov, A. V., Zaikova, T. O., Birrell, G. B., Keana, J. F. W., & Griffith, O. H. (1999) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(99)00166-3 · Cited by 19
Phosphorothiolate Analogues of Phosphatidylinositols as Assay Substrates for Phospholipase C
Liu, Y., Mihai, C., Kubiak, R. J., Rebecchi, M. J., & Bruzik, K. S. (2007) · ChemBioChem · doi:10.1002/cbic.200700061 · Cited by 14
Auto-inhibition and phosphorylation-induced activation of PLC-gamma isozymes
Hajicek, N., & Sondek, J. (2013) · Worldwide Protein Data Bank · doi:10.2210/pdb4k44/pdb · Cited by 11
Wang, X., Barrett, M. O., Sondek, J., Harden, T. K., & Zhang, Q. (2012) · Biochemistry · doi:10.1021/bi300637h · Cited by 8
Cited by
Sorted by citations
Comprehensive review of targeted therapy for colorectal cancer
Xie, Y.-H., Chen, Y.-X., & Fang, J.-Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0116-z · Cited by 1,687
Integrated molecular analysis of adult T cell leukemia/lymphoma
Kataoka, K., Nagata, Y., Kitanaka, A., Shiraishi, Y., Shimamura, T., Yasunaga, J., Totoki, Y., Chiba, K., Sato‐Otsubo, A., Nagae, G., et al. (2015) · Nature Genetics · doi:10.1038/ng.3415 · Cited by 844
The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease
Berridge, M. J. (2016) · Physiological Reviews · doi:10.1152/physrev.00006.2016 · Cited by 779
Neutrophils as emerging therapeutic targets
Németh, T., Sperandio, M., & Mócsai, A. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0054-z · Cited by 676
Lipid metabolism in cancer progression and therapeutic strategies
Fu, Y., Zou, T., Shen, X., Nelson, P. J., Li, J., Wu, C., Yang, J., Zheng, Y., Bruns, C. J., Zhao, Y., et al. (2020) · MedComm · doi:10.1002/mco2.27 · Cited by 428
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
