Structural insights and activating mutations in diverse pathologies define mechanisms of deregulation for phospholipase C gamma enzymes
Open accessAbstract
BACKGROUND: PLCγ enzymes are key nodes in cellular signal transduction and their mutated and rare variants have been recently implicated in development of a range of diseases with unmet need including cancer, complex immune disorders, inflammation and neurodegenerative diseases. However, molecular nature of activation and the impact and dysregulation mechanisms by mutations, remain unclear; both are critically dependent on comprehensive characterization of the intact PLCγ enzymes. METHODS: For structural studies we applied cryo-EM, cross-linking mass spectrometry and hydrogen-deuterium exchange mass spectrometry. In parallel, we compiled mutations linked to main pathologies, established their distribution and assessed their impact in cells and in vitro. FINDINGS: We define structure of a complex containing an intact, autoinhibited PLCγ1 and the intracellular part of FGFR1 and show that the interaction is centred on the nSH2 domain of PLCγ1. We define the architecture of PLCγ1 where an autoinhibitory interface involves the cSH2, spPH, TIM-barrel and C2 domains; this relative orientation occludes PLCγ1 access to its substrate. Based on this framework and functional characterization, the mechanism leading to an increase in PLCγ1 activity for the largest group of mutations is consistent with the major, direct impact on the autoinhibitory interface. INTERPRETATION: We reveal features of PLCγ enzymes that are important for determining their activation status. Targeting such features, as an alternative to targeting the PLC active site that has so far not been achieved for any PLC, could provide new routes for clinical interventions related to various pathologies driven by PLCγ deregulation. FUND: CR UK, MRC and AstaZeneca.
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
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?
Following phosphorylation of PLCγ1, the critical pTyr residue binds to its cSH2 domain, and this intramolecular interaction is required for repositioning of the regulatory region and release of autoinhibition.
“Following phosphorylation of PLCγ1, the critical pTyr residue in PLCγ1 binds to its cSH2 domain; this intramolecular interaction is required for repositioning of the regulatory region and release of the autoinhibition.”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [48]
The Discussion (page unavailable) says that previous studies suggest phosphorylated Y783 binds the cSH2 domain, resulting in release of autoinhibition. It does not establish that this binding is required to reposition the regulatory region; instead, it says the changes that bring Y783 and cSH2 together remain unclear. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPLCγ1 shares 52% sequence identity with PLCγ2, and their overall domain organisation is conserved; therefore, homology models are plausible.
“PLCγ1 shares 52% sequence identity with PLCγ2, and their overall domain organisation is conserved; therefore, homology models are plausible.”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Liu et al., 2020
The Results section on PLCγ1 architecture (page unavailable) describes PLCγ-family domains and reports using conserved PLC-core structures to make a homology model of PLCγ1. It does not give 52% sequence identity between PLCγ1 and PLCγ2 or explicitly establish that their overall domain organisation is conserved. (LLM, conf=0.84)
Experimental — accuracy not yet measuredInitial cellular studies of individual mutations, as well as their comparison in a standard cell-based assay, have shown a clear increase in basal PLC activity of these variants and further enhancement after stimulation.
“Initial cellular studies of individual mutations, as well as their comparison in a standard cell-based assay, have shown a clear increase in basal PLC activity of these variants and further enhancement after stimulation [(Liu et al., 2020); Fig S1].”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Liu et al., 2020
The Results section (‘Distribution and functional impact of mutations in PLCγ enzymes’; page unavailable) reports increased activity for the majority of variants tested in a standard cellular assay, and says most were further stimulated by EGF. It also identifies several deletions that lost responsiveness to EGF, so further enhancement does not apply to every tested variant. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn inactive PLCγ1, cSH2 and sPH domains contribute to autoinhibition by interacting with the PLC-core, preventing membrane interactions required for access to PI(4,5)P2.
“In the inactive form, two domains within the regulatory region (cSH2 and sPH) directly contribute to autoinhibition by interacting with the PLC-core, preventing membrane interactions required for the access to the PLC substrate, PI(4,5)P2 [47,48].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [48]
Positions of the SH3 domain in the γSA are different in the two PLCγ2 models, as expected from studies of PLCγ1 suggesting flexibility of this domain.
“Positions of the SH3 domain in the γSA are different in the two models (Fig. 1B), as expected from studies of PLCγ1 that suggested flexibility of this domain with respect to the rest of the molecule (Liu et al., 2020).”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Liu et al., 2020
There are currently no structures for the full-length PLCγ2 molecule, but useful information can be inferred from the recently-published crystal and cryo-electron microscopy (cryoEM) structures of the closely related PLCγ1 molecule.
“Conversely, there are currently no structures for the full-length PLCγ2 molecule, but we can infer some useful information from the recently-published crystal and cryo-electron microscopy (cryoEM) structures of the closely related PLCγ1 molecule [83, 84].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [84]
The partner protein could be a RTK or a phosphotyrosine motif associated with an adaptor protein, such as LAT in T-cells, or BLNK in B-cells.
“The partner protein could be a RTK [84, 88] or a phosphotyrosine motif associated with an adaptor protein, such as LAT in T-cells [72], or BLNK in B-cells [89].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [84]
The crystal and cryoEM structures reveal how the catalytic and γSA regions interact, thus maintaining PLCγ in an autoinhibited state.
“The crystal and cryoEM structures reveal how the catalytic and γSA regions interact, thus maintaining PLCγ in an autoinhibited state [83, 84].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [84]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
MotionCor2 - anisotropic correction of beam-induced motion for improved cryo-electron microscopy
Zheng, S., Palovcak, E. J., Armache, J., Verba, K., Cheng, Y.-F., & Agard, D. (2017) · Nature Methods · doi:10.1038/nmeth.4193 · Cited by 7,678 · see citing works
New tools for automated high-resolution cryo-EM structure determination in RELION-3
Zivanov, J., Nakane, T., Forsberg, B., Kimanius, D., Hagen, W., Lindahl, E., & Scheres, S. (2018) · eLife · doi:10.7554/elife.42166 · Cited by 4,377 · see citing works
Gctf: Real-time CTF determination and correction
Zhang, K. (2015) · Journal of Structural Biology · doi:10.1016/j.jsb.2015.11.003 · Cited by 3,372 · see citing works
Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation
Balla, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00028.2012 · Cited by 1,638 · see citing works
de Lange, K. M., Moutsianas, L., Lee, J. C., Lamb, C. A., Luo, Y., Kennedy, N. A., Jostins, L., Rice, D. L., Gutierrez-Achury, J., Ji, S.-G., et al. (2017) · Nature Genetics · doi:10.1038/ng.3760 · Cited by 1,445 · see citing works
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 · see citing works
ARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · see citing works
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 819 · see citing works
The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease
Berridge, M. J. (2016) · Physiological Reviews · doi:10.1152/physrev.00006.2016 · Cited by 757 · see citing works
Masson, G. R., Burke, J. E., Ahn, N. G., Anand, G. S., Borchers, C. H., Brier, S., Bou-Assaf, G. M., Engen, J. R., Englander, S. W., Faber, J. H., et al. (2019) · Nature Methods · doi:10.1038/s41592-019-0459-y · Cited by 733 · see citing works
Self-citationCold Urticaria, Immunodeficiency, and Autoimmunity Related to <i>PLCG2</i> 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 · see citing works
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 · see citing works
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 · see citing works
Self-citationAutomated Assignment of MS/MS Cleavable Cross-Links in Protein 3D-Structure Analysis
Götze, M., Pettelkau, J., Fritzsche, R., Ihling, C. H., Schäfer, M., & Sinz, A. (2014) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-014-1001-1 · Cited by 242 · see citing works
Recurrent CIC Gene Abnormalities in Angiosarcomas
Huang, S., Zhang, L., Sung, Y., Chen, C., Kao, Y., Agaram, N. P., Singer, S., Tap, W. D., D’Angelo, S. P., & Antonescu, C. R. (2016) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000582 · Cited by 207 · see citing works
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 · see citing works
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 · see citing works
HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome
Gbadegesin, R., Adeyemo, A., Webb, N. J. A., Greenbaum, L. A., Abeyagunawardena, A. S., Thalgahagoda, S., Kale, A. S., Gipson, D. S., Srivastava, T., Lin, J., et al. (2014) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014030247 · Cited by 144 · 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 · cited 1× · see citing works
“Interestingly, in a number of cases where functional characterization of the effect of genetic changes on PLC activity has been performed, these alterations (predominantly single amino-acid substitutions) result in an increase of PLCg activity [6,8,14,15].”
BackgroundSelf-citation(2016) · Elsevier eBooks · doi:10.1016/c2011-1-06109-x · Cited by 143 · see citing works
Phospholipase C δ1 requires a pleckstrin homology domain for interaction with the plasma membrane
Paterson, H. F., Savopoulos, J. W., Perišić, O., Cheung, R., Ellis, M. V., Williams, R. L., & Katan, M. (1995) · Biochemical Journal · doi:10.1042/bj3120661 · Cited by 121 · see citing works
Self-citationDESGESCO (Dementia Genetics Spanish Consortium), E. (. D. E. D. B., van der Lee, S. J., biobank), E. (. D. E. D., IFGC (International FTD-Genomics Consortium), I. (. I. P. D. G. C., IPDGC (The International Parkinson Disease Genomics Consortium), Dementia), R.-F. (. A. M. F. I. F.-T., (NBB), N. B. B., The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Conway, O. J., Jansen, I., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02026-8 · Cited by 120 · see citing works
Dysfunction of phospholipase Cγ in immune disorders and cancer
Koss, H., Bunney, T. D., Behjati, S., & Katan, M. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.09.004 · Cited by 115 · see citing works
Self-citationBunney, 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 · see citing works
Self-citationA quantitative liposome microarray to systematically characterize protein-lipid interactions
Saliba, A., Vonkova, I., Ceschia, S., Findlay, G. M., Maeda, K., Tischer, C., Deghou, S., van Noort, V., Peer Bork, B., Pawson, T. J., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2734 · Cited by 80 · see citing works
Self-citationNovel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa
Neves, J. F., Doffinger, R., Barcena-Morales, G., Martins, C., Papapietro, O., Plagnol, V., Curtis, J., Martins, M., Kumararatne, D., Cordeiro, A. I., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02863 · Cited by 79 · see citing works
Self-citationJones, D., Woyach, J. A., Zhao, W., Caruthers, S., Tu, H., Coleman, J., Byrd, J. C., Johnson, A. J., & Lozanski, G. (2017) · Leukemia · doi:10.1038/leu.2017.110 · Cited by 71 · see citing works
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 · see citing works
Self-citationTwo FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ
Huang, Z., Marsiglia, W. M., Roy, U. B., Rahimi, N., Ilghari, D., Wang, H., Chen, H., Gai, W., Blais, S. P., Neubert, T. A., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.11.010 · Cited by 59 · see citing works
Bala, K., Bosco, R., Gramolelli, S., Haas, D. A., Kati, S., Pietrek, M., Hävemeier, A., Yakushko, Y., Singh, V. V., Dittrich‐Breiholz, O., et al. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002927 · Cited by 59 · see citing works
Modeling Protein Complexes Using Restraints from Crosslinking Mass Spectrometry
Bullock, J. M. A., Sen, N., Thalassinos, K., & Topf, M. (2018) · Structure · doi:10.1016/j.str.2018.04.016 · Cited by 58 · see citing works
Walliser, C., Wist, M., Hermkes, E., Zhou, Y., Schade, A., Haas, J., Deinzer, J., Désiré, L., Li, S. S. C., Stilgenbauer, S., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.26173 · Cited by 17 · see citing works
Dynamic Allostery in PLCγ1 and Its Modulation by a Cancer Mutation Revealed by MD Simulation and NMR
Koss, H., Bunney, T. D., Esposito, D., Martins, M., Katan, M., & Driscoll, P. C. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2018.05.031 · Cited by 10 · see citing works
Self-citationEverett, K. L., & Katan, M. (2016) · Encyclopedia of Cell Biology · doi:10.1016/b978-0-12-394447-4.30017-7 · Cited by 3 · see citing works
Self-citation
Flagged first, then by citations
1 of the 35 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane
Katan, M., & Cockcroft, S. (2020) · Essays in Biochemistry · doi:10.1042/ebc20200041 · Cited by 176 · see citing works
Self-citationPhospholipase C families: Common themes and versatility in physiology and pathology
Katan, M., & Cockcroft, S. (2020) · Progress in Lipid Research · doi:10.1016/j.plipres.2020.101065 · Cited by 89 · see citing works
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-citationMartín-Nalda, A., Fortuny, C., Rey, L., Bunney, T. D., Alsina, L., Esteve-Solé, A., Bull, D., Anton, M. C., Basagaña, M., Casals, F., et al. (2020) · Journal of Clinical Immunology · doi:10.1007/s10875-020-00794-7 · Cited by 56 · see citing works
“Considerable supporting evidence is consistent with a model where PLCγ2 is kept in an inactive state by extensive intramolecular interactions between the regulatory domains (including cSH2 and spPH domains) and the PLC-core domains [11, 31].”
BackgroundMethodSelf-citationPleckstrin Homology [PH] domain, structure, mechanism, and contribution to human disease
Powis, G., Meuillet, E. J., Indarte, M., Booher, G., & Kirkpatrick, L. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115024 · Cited by 50 · see citing works
Activation Mechanisms and Diverse Functions of Mammalian Phospholipase C
Kanemaru, K., & Nakamura, Y. (2023) · Biomolecules · doi:10.3390/biom13060915 · Cited by 51 · see citing works
Emerging roles of PLCγ1 in endothelial biology
Chen, D.-Y., & Simons, M. (2021) · Science Signaling · doi:10.1126/scisignal.abc6612 · Cited by 34 · see citing works
The rapidly evolving role of cryo-EM in drug design
Wigge, C., Stefanovic, A., & Radjainia, M. (2020) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2020.12.003 · Cited by 34 · see citing works
Mechanism of activation and the rewired network: New drug design concepts
Nussinov, R., Zhang, M., Maloney, R., Tsai, C., Yavuz, B. R., Tunçbağ, N., & Jang, H. (2021) · Medicinal Research Reviews · doi:10.1002/med.21863 · Cited by 30 · see citing works
G-CSF drives autoinflammation in APLAID
Mulazzani, E., Kong, K., Aróstegui, J. I., Ng, A. P., Ranathunga, N., Abeysekera, W., Garnham, A. L., Ng, S., Baker, P. J., Jackson, J. T., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01473-6 · Cited by 24 · see citing works
Le Huray, K. I. P., Bunney, T. D., Pinotsis, N., Kalli, A. C., & Katan, M. (2022) · Science Advances · doi:10.1126/sciadv.abp9688 · Cited by 21 · see citing works
Self-citationDynamics of allosteric regulation of the phospholipase C-γ isozymes upon recruitment to membranes
Siraliev-Perez, E., Stariha, J. T., Hoffmann, R. M., Temple, B. R., Zhang, Q., Hajicek, N., Jenkins, M. L., Burke, J. E., & Sondek, J. (2022) · eLife · doi:10.7554/elife.77809 · Cited by 18 · see citing works
Li, K., Ran, B., Wang, Y., Liu, L., & Li, W. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.999061 · Cited by 18 · see citing works
Wada, J., Rathnayake, U. M., Jenkins, L. M. M., Singh, A. K., Mohammadi, M., Appella, E., Randazzo, P. A., & Samelson, L. E. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101680 · Cited by 15 · see citing works
Khan, S. M., Faisal, A.-R. M., Nila, T. A., Binti, N. N., Hosen, M. I., & Shekhar, H. U. (2021) · PLoS ONE · doi:10.1371/journal.pone.0260054 · Cited by 13 · see citing works
Conformational switches that control the TEC kinase – PLCγ signaling axis
Lowe, J., Joseph, R. E., & Andreotti, A. H. (2022) · Journal of Structural Biology X · doi:10.1016/j.yjsbx.2022.100061 · Cited by 12 · see citing works
Prawiro, C., Bunney, T. D., Kampyli, C., Yaguchi, H., Katan, M., & Bangham, C. R. M. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166601 · Cited by 11 · see citing works
Self-citationThe Conformational State of the BTK Substrate PLCγ Contributes to Ibrutinib Resistance
Joseph, R. E., Lowe, J., Fulton, D. B., Engen, J. R., Wales, T. E., & Andreotti, A. H. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167422 · Cited by 6 · see citing works
Characterisation of molecular mechanisms for PLCγ2 disease-linked variants
Bunney, T. D., Kampyli, C., Gregory, A., & Katan, M. (2024) · Advances in Biological Regulation · doi:10.1016/j.jbior.2024.101053 · Cited by 8 · see citing works
Self-citationDuarte-Pereira, S., Matos, S., Oliveira, J. L., & Silva, R. M. (2023) · Berichte aus der medizinischen Informatik und Bioinformatik/Journal of integrative bioinformatics · doi:10.1515/jib-2022-0049 · Cited by 8 · see citing works
Shin, Y.-C., Plummer-Medeiros, A. M., Mungenast, A., Choi, H.-W., TenDyke, K., Zhu, X., Shepard, J., Sanders, K., Zhuang, N., Hu, L., et al. (2024) · Science Advances · doi:10.1126/sciadv.adn6037 · Cited by 7 · see citing works
Nosbisch, J. L., Bear, J. E., & Haugh, J. M. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101886 · Cited by 7 · see citing works
Samarina, N., Ssebyatika, G. L., Tikla, T., Waldmann, J.-Y., Abere, B., Nanna, V., Marasco, M., Carlomagno, T., Krey, T., & Schulz, T. F. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009635 · Cited by 6 · see citing works
T Cell Receptor Pathway Mutations in Mature T Cell Lymphomas
Zhang, Y., Cheng, K., & Choi, J. (2023) · Journal of Immunology · doi:10.4049/jimmunol.2200682 · Cited by 4 · see citing works
Phosphoinositide-specific phospholipase C enzymes: Recent advances in a long journey
Macrae, C., Lalović, D., Bunney, T. D., & Katan, M. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2025.159627 · Cited by 4 · see citing works
Self-citationPierangelini, A., Kessler, B. M., & O'Brien, D. P. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101017 · Cited by 3 · see citing works
Mariano, A., Ammendola, S., Migliorini, A., Leopizzi, M., Raimondo, D., & d’Abusco, A. S. (2024) · Cell Biochemistry and Function · doi:10.1002/cbf.4091 · Cited by 4 · see citing works
Bull, D., Matte, J. C., Navarron, C. M., McIntyre, R., Whiting, P., Katan, M., Ducotterd, F., & Magno, L. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166978 · Cited by 3 · see citing works
Self-citationHeterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune functionPreprint
Ma, M., Zheng, Y., Deng, M., Lu, S., Pan, X., Luo, X., Etoundi, M., Li‐Kroeger, D., Worley, K. C., Burrage, L. C., et al. (2024) · eLife · doi:10.7554/elife.95887 · Cited by 3 · see citing works
Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune function
Ma, M., Zheng, Y., Deng, M., Lu, S., Pan, X., Luo, X., Etoundi, M., Li‐Kroeger, D., Worley, K. C., Burrage, L. C., et al. (2025) · eLife · doi:10.7554/elife.95887.3 · Cited by 2 · see citing works
Targeting G-CSF to treat autoinflammation
Bunney, T. D., & Katan, M. (2023) · Nature Immunology · doi:10.1038/s41590-023-01474-5 · Cited by 2 · see citing works
Self-citationRaghunathan, V. M., Fan, G., Kittai, A. S., Okada, C. Y., Danilov, A. V., & Spurgeon, S. E. F. (2020) · European Journal Of Haematology · doi:10.1111/ejh.13538 · Cited by 2 · see citing works
LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation
Ren, H., Lee, H., Omar, Y. A. D., DeGrandchamp, J. B., Hung, C., Eisen, T. J., Stamou, D. G., Kuriyan, J., Chakraborty, A. K., & Groves, J. T. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2614738123
The NAD Interactome, Identification of Putative New NAD-Binding Proteins
Duarte-Pereira, S., Matos, S., Oliveira, J. L., & Silva, R. M. (2022) · Lecture notes in networks and systems · doi:10.1007/978-3-031-17024-9_5 · Cited by 1 · see citing works
Molecular insight into the autoinhibition of a master regulator of lipid signalling in human disease
Burke, J. E. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102634
Physiological Roles of Phospholipase Cγ and Its Mutations in Human Disease
Jang, H., Choi, J. H., & Chang, J. (2020) · Scholarworks@UNIST (Ulsan National Institute of Science and Technology) · doi:10.5352/jls.2020.30.9.826
Lyon, A. M., Fisher, I. J., & Garland‐Kuntz, E. E. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819460-7.00063-3
Ma, M., Zheng, Y., Lu, S., Pan, X., Worley, K. C., Burrage, L. C., Blieden, L. S., Allworth, A., Chen, W.-L., Merla, G., et al. (2024) · eLife · doi:10.7554/elife.95887.1
Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune functionPreprint
Ma, M., Zheng, Y., Deng, M., Lu, S., Pan, X., Luo, X., Etoundi, M., Li‐Kroeger, D., Worley, K. C., Burrage, L. C., et al. (2025) · eLife · doi:10.7554/elife.95887.2
Bunney, T. D., Nyvall, H. G., Macrae, C., Lalović, D., Gregory, A., Huray, K. I. P. L., Harvey, N., Pinotsis, N., Kalli, A. C., Waudby, C. A., et al. (2025) · Biochemical Journal · doi:10.1042/bcj20253358
Self-citationChen, C., Liu, K., Xiang, M., & Zhang, X. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2026.1860227
- Authors
- Liu, Y., Bunney, T. D., Khosa, S., Macé, K., Beckenbauer, K., Askwith, T., Maslen, S., Stubbs, C., de Oliveira, T. M., Sader, K., Skehel, M., Gavin, A.-C., Phillips, C., & Katan, M.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- Institute of Structural and Molecular Biology (GB)
- European Molecular Biology Laboratory (DE)
- UCL School of Pharmacy (GB)
- MRC Laboratory of Molecular Biology (GB)
- Thermo Fisher Scientific (United Kingdom) (GB)
- University of Geneva (CH)
- Corresponding author
- Bunney, Tom D.
- Phillips, Christopher
- Katan, Matilda
- ORCID
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 51
- Pages
- 102607
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC7000336
- OpenAlex
- W2999670393
- Cited by
- 42
- References
- 35
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 8
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Cancer Research UK
- AbbVie Deutschland
- Medical Research Council (P028160)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- phospholipase C-gamma, PLCγ1, autoinhibition, C2 domain, FGFR1, protein complex structure, activating mutations, signal transduction, disease-associated variants, cancer, neurodegenerative diseases, immune disorders, inflammation
- MeSH terms
- Humans, Models, Molecular, Mutation, Protein Binding, Mutant Proteins, Receptor, Fibroblast Growth Factor, Type 1, 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
