Disease relevance of PLCG1

• Chronic pancreatitis is associated with increased concentrations of epidermal growth factor receptor, transforming growth factor alpha, and phospholipase C gamma [1].
• The epidermal growth factor receptor is associated with phospholipase C-gamma 1 in meningiomas [2].
• PymT variants unable to bind PI3K and PLCgamma-1 directly induced hemangiomas similarly to wild type, but a mutant unable to bind ShcA was transformation compromised [3].
• We determined the relative content of PLC-gamma 1 in primary human mammary carcinomas and in nonmalignant mammary tissues [4].
• Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas [4].

Psychiatry related information on PLCG1

• The phospholipase C-gamma1 gene (PLCG1) and lithium-responsive bipolar disorder: re-examination of an intronic dinucleotide repeat polymorphism [5].
• Densitometric analysis of the bands demonstrated decreased expression levels of PLCbeta1 and PLCgamma, a non-related phospholipase which is a substrate of tyrosine kinase, in CJD cases when compared with controls [6].

High impact information on PLCG1

• The pathway by which Golgi-associated Ras becomes activated involves PLCgamma and RasGRP1 and may also require retrograde trafficking of Ras from the plasma membrane to the Golgi as a consequence of depalmitoylation [7].
• Receptor associated src-family kinases which are activated following receptor cross-linking, also associate with downstream effectors, including phospholipase C gamma (PLC gamma), p21ras [8].
• CD28 receptor ligation induces tyrosine phosphorylation of specific substrates, including phospholipase C gamma 1, and triggers both calcium-dependent and calcium-independent signals [9].
• P2-purinergic stimulation increases cAMP by activating adenylyl cyclase isoform V. It also involves tyrosine kinases to activate phospholipase C-gamma to produce inositol 1,4,5-trisphosphate and Cl(-)/HCO(3)(-) exchange to induce a large transient acidosis [10].
• Phosphorylation of this site mediates intermediate- to high-affinity interactions with multiple SH2-containing signal transducers, including phosphatidylinositol 3-kinase, phospholipase C gamma, pp60c-src, and the GRB-2-Sos complex [11].

Chemical compound and disease context of PLCG1

• Thus, these data are consistent with the possibility that the EGF receptor tyrosine kinase regulates PLC-gamma 1 activity in native meningioma tissue [2].
• In two of three meningiomas EGF receptors and/or a 170-kd phosphotyrosine band precipitated with a PLC-gamma 1 antiserum [2].
• Phospholipase C-gamma 1 catalytic activity, measured in a PIP2 hydrolysis assay, was higher in nine EGF receptor-positive meningiomas than in six EGF receptor-negative meningiomas (P = .05; t test) [2].
• We confirm that phosphoinositide turnover is regulated by a pertussis toxin (PT)-sensitive G protein, most probably by controlling phosphorylation of phospholipase C-gamma 1 [12].
• The kinetic mechanism of the trk receptor-linked tyrosine kinase was determined using a baculovirus expressed trk kinase domain and a bacterially expressed phospholipase C-gamma/glutathione S-transferase (PLC-gamma/ GST) fusion protein as substrate [13].

Biological context of PLCG1

• The overall distribution of the PLCG1 dinucleotide repeat alleles was not significantly different between different categories of subjects [5].
• Tyrosine phosphorylation of PLC-gamma was not induced by bombesin, TPA, or insulin [14].
• Our results show that purified SH2 domains of PLC gamma are able to prevent tyrosine dephosphorylation of the EGF receptor and other receptors with tyrosine activity [15].
• In this study, we have identified the Rac-GAP beta2-chimaerin as an effector of the epidermal growth factor receptor (EGFR) via coupling to phospholipase Cgamma (PLCgamma) and generation of the lipid second messenger diacylglycerol (DAG) [16].
• This phosphorylation event, mediated by a putative protein tyrosine kinase coupled to the antigen receptor, probably stimulates the enzymatic activity of PLC-gamma 1, thereby promoting inositol phospholipid hydrolysis and other downstream signal transduction events [17].

Anatomical context of PLCG1

• After stimulation of the TCR on Jurkat T cells, tyrosine-phosphorylated proteins of 36, 38, 58, and 63 kD coprecipitate with PLC gamma 1 [18].
• These studies establish that p56lck associates with PLC gamma 1 as a result of TCR stimulation of Jurkat cells, suggesting that p56lck plays a central role in coupling the TCR to the activation of PLC gamma 1 [18].
• These results suggest that Fc gamma R-initiated phosphoinositide turnover in human NK cells is regulated by the tyrosine phosphorylation of PLC-gamma [19].
• The triggering of T- or B-cell antigen-specific receptors is accompanied by rapid tyrosine phosphorylation of distinct cellular substrates, one of which is the gamma 1 isoform of inositol phospholipid-specific phospholipase C (PLC-gamma 1) [17].
• A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1 [20].

Associations of PLCG1 with chemical compounds

• (1998) recently published preliminary evidence suggesting that bipolar patients with an excellent response to lithium treatment have a higher frequency of a specific dinucleotide repeat allele in the phospholipase Cgamma-1 (PLCG1) genomic region [5].
• This relocalization and association with Rac1 were impaired by disruption of the beta2-chimaerin C1 domain as well as by PLCgamma1 RNAi, thus defining beta2-chimaerin as a novel DAG effector [16].
• In addition, the dominant-negative PLC gamma-1 fragment did not diminish EGF-induced thymidine incorporation [21].
• Characterization of PDGFR mutants in which these phosphorylation sites are substituted with phenylalanine (F) indicated that Y-1021 and Y-1009 were required for the stable association of PLC gamma and a 64-kDa protein, respectively [22].
• In primary cultures of human mast cells, Fc epsilon RI aggregation induced a rapid translocation and phosphorylation of PLC gamma 1, and subsequent inositol trisphosphate (IP3) production, which preceded PI 3-kinase-related signals [23].

Physical interactions of PLCG1

• GIT1 interacts with PLCgamma via a novel Spa homology domain (SHD) and a coiled-coil domain [24].
• PLC-gamma is bound to CAIR-1/BAG-3 in unstimulated cells [25].
• The Grb2 adapter protein was detected in complex with hSos / PLCgamma1, suggesting a regulatory role for Grb2 [26].
• The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma [27].
• Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma [28].
• An inhibitory peptide, which binds to the Src homology 2 domains contained in PLC-gamma without interrupting binding of PLC-gamma to NHE3, was used to probe a non-lipase-dependent role of PLC-gamma [29].

Enzymatic interactions of PLCG1

• Indeed, purified PDGF or EGF receptor phosphorylated purified PLC-gamma on tyrosines identical to those phosphorylated in vivo [14].
• PKC mu can down-regulate the ability of Syk to phosphorylate PLC gamma 1 in vitro [30].
• The C-terminal half of the PLC-gamma split PH domain has been implicated to interact directly with the TRPC3 calcium channel, thereby providing a direct coupling mechanism between PLC-gamma and agonist-induced calcium entry [31].
• In addition, phospholipase Cgamma1 (PLCgamma1) and PLCgamma2 were tyrosine phosphorylated upon Ag stimulation in CD45- cells, despite much reduced inositol trisphosphate production and lack of calcium mobilization [32].
• Unglycosylated TrkA core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules Shc and PLC-gamma [33].

Regulatory relationships of PLCG1

• Lastly, anti-sense oligonucleotides (20 microM) to PLC gamma-1 reduced both responses in NR6 cells expressing wild-type EGFR [21].
• Since tyrosine phosphorylation of PLC gamma enhances its enzymatic activity, we speculated that PDGFR mutants that failed to activate PLC gamma were unable to mediate its tyrosine phosphorylation [22].
• The Rac1-activated PKNgamma in turn increases threonine (but not serine) phosphorylation of phospholipase C (PLC) gamma1 and up-regulates PLCgamma1 activity leading to the onset of intracellular Ca(2+) mobilization [34].
• Focal adhesion kinase-related fakB is regulated by the integrin LFA-1 and interacts with the SH3 domain of phospholipase C gamma 1 [35].
• The GTPase-activating protein of Ras suppresses platelet-derived growth factor beta receptor signaling by silencing phospholipase C-gamma 1 [36].

Other interactions of PLCG1

• In vitro phosphorylation of fusion proteins showed that both Syk and PLC gamma 1 are potential substrates of PKC mu in vivo [30].
• Thus, GAP functions to suppress signal relay by the beta PDGFR, and it does so by silencing PLC gamma [36].
• The SH2 domains of Grb2 and PLC-gamma 1 were required for the formation of this protein complex [37].
• These data provide evidence for a VEGF-R2-, phospholipase C-gamma-, and PKCalpha/epsilon-mediated cytoprotective pathway in ECs [38].
• PKCtheta activated NF-kappaB in SLP-76- and PLCgamma1-deficient cells, showing that PKCtheta is acting further downstream [39].

Analytical, diagnostic and therapeutic context of PLCG1

• Immunoblotting analyses with PLC-gamma 1- and PLC-gamma 2-specific antisera demonstrate that both isoforms are expressed in human NK cells [19].
• TCR stimulation leads to an association between the SH2 domains of PLC gamma 1 and a protein tyrosine kinase, which, by peptide mapping, is identical to p56lck [18].
• Phospholipase C gamma (PLC gamma) is among the candidate transducers of this signal because of its potential roles in modulating cytoskeletal dynamics [21].
• By immunohistochemistry, the EGF receptor, TGF alpha, and PLC gamma 1 were found to be expressed at high concentrations in pancreatic ductal and acinar cells from chronic pancreatitis patients [1].
• The SH2 domain from Grb2 formed an association with the hSos / PLCgamma1 complex, which was enhanced following TCR / CD3 ligation [26].

References