Molecule Information

General Information of the Molecule (ID: Mol00567)
Name
Phosphoinositide phospholipase C-gamma-2 (PLCG2) ,Homo sapiens
Synonyms
Phosphoinositide phospholipase C-gamma-2; Phospholipase C-IV; PLC-IV; Phospholipase C-gamma-2; PLC-gamma-2
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Molecule Type
Protein
Gene Name
PLCG2
Gene ID
5336
Location
chr16:81739097-81962685[+]
Sequence
MSTTVNVDSLAEYEKSQIKRALELGTVMTVFSFRKSTPERRTVQVIMETRQVAWSKTADK
IEGFLDIMEIKEIRPGKNSKDFERAKAVRQKEDCCFTILYGTQFVLSTLSLAADSKEDAV
NWLSGLKILHQEAMNASTPTIIESWLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSA
KFLKDKFVEIGAHKDELSFEQFHLFYKKLMFEQQKSILDEFKKDSSVFILGNTDRPDASA
VYLHDFQRFLIHEQQEHWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRENS
IWDEKYDAVDMQDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDC
WDGPDGKPVIYHGWTRTTKIKFDDVVQAIKDHAFVTSSFPVILSIEEHCSVEQQRHMAKA
FKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKLGPRGDVDVNMEDKKDEHKQQGE
LYMWDSIDQKWTRHYCAIADAKLSFSDDIEQTMEEEVPQDIPPTELHFGEKWFHKKVEKR
TSAEKLLQEYCMETGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYY
LTDNLTFSSIYALIQHYRETHLRCAEFELRLTDPVPNPNPHESKPWYYDSLSRGEAEDML
MRIPRDGAFLIRKREGSDSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSYY
EKHSLYRKMRLRYPVTPELLERYNMERDINSLYDVSRMYVDPSEINPSMPQRTVKALYDY
KAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVEDISTADFEELEKQII
EDNPLGSLCRGILDLNTYNVVKAPQGKNQKSFVFILEPKQQGDPPVEFATDRVEELFEWF
QSIREITWKIDTKENNMKYWEKNQSIAIELSDLVVYCKPTSKTKDNLENPDFREIRSFVE
TKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKY
MQMNHALFSLNGRTGYVLQPESMRTEKYDPMPPESQRKILMTLTVKVLGARHLPKLGRSI
ACPFVEVEICGAEYDNNKFKTTVVNDNGLSPIWAPTQEKVTFEIYDPNLAFLRFVVYEED
MFSDPNFLAHATYPIKAVKSGFRSVPLKNGYSEDIELASLLVFCEMRPVLESEEELYSSC
RQLRRRQEELNNQLFLYDTHQNLRNANRDALVKEFSVNENQLQLYQEKCNKRLREKRVSN
SKFYS
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Function
The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. It is a crucial enzyme in transmembrane signaling.
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Uniprot ID
PLCG2_HUMAN
Ensembl ID
ENSG00000197943
HGNC ID
HGNC:9066
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Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
1 drug(s) in total
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Ibrutinib
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Chronic lymphocytic leukemia [1]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
 Disease Info 
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.S707Y
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Disease Class: Chronic lymphocytic leukemia [1]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
 Disease Info 
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.P664W
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Disease Class: Chronic lymphocytic leukemia [1]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
 Disease Info 
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.P664S
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Disease Class: Chronic lymphocytic leukemia [1]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
 Disease Info 
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Missense mutation
p.L845F
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
NF-kB signaling pathway Inhibition hsa04218
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; Next-generation sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
Mechanism Description All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.
Disease Class: Chronic lymphocytic leukemia [2]
Resistant Disease Chronic lymphocytic leukemia [ICD-11: 2A82.0]
 Disease Info 
Resistant Drug Ibrutinib
 Drug Info 
Molecule Alteration Mutation
p.R665W+p.L845F+p.S707Y
Experimental Note Revealed Based on the Cell Line Data
Mechanism Description In contrast to the BTKC481S mutation, which causes eventual loss of BTK inhibition by ibrutinib, PLCG2 mutations are all potentially gain-of-function mutations. Situated downstream from BTK, PLCG2 mutations allow for continued signalling regardless of BTK activity. After stimulation with anti-IgM antibody, cells with either the PLCG2R665W or PLCG2L845F mutations were found to have sustained BCR signalling that was not inhibited by ibrutinib, as measured by calcium-flux assays and phosphorylation of ERK and AKT.
References
Ref 1 Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017 Mar 16;129(11):1469-1479. doi: 10.1182/blood-2016-06-719294. Epub 2017 Jan 3.
Ref 2 Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma .Br J Haematol. 2015 Aug;170(4):445-56. doi: 10.1111/bjh.13427. Epub 2015 Apr 9. 10.1111/bjh.13427

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