Disease relevance of PLCG2

• Activation of human neutrophils by Mycobacterium tuberculosis H37Ra involves phospholipase C gamma 2, Shc adapter protein, and p38 mitogen-activated protein kinase [1].
• We obtained the full-length cDNA for human PLCgamma2 and expressed it in E. coli using the expression vector pT5T [2].
• Here we present evidence that exposure of DT40 lymphoma B-cells to low energy electromagnetic fields (EMF) results in activation of phospholipase C-gamma 2 (PLC-gamma2), leading to increased inositol phospholipid turnover [3].
• In contrast, crosslinking of sIg on cells infected with EBV recombinants with null mutations in LMP2A results in transient tyrosine phosphorylation of lyn, syk, phospholipase C gamma 2 and phosphatidylinositol-3' kinase, transiently increased intracellular free calcium, and reactivation of lytic EBV infection [4].

High impact information on PLCG2

• The best characterized of the intranuclear lipids are the inositol lipids that form the components of a phosphoinositide-phospholipase C cycle [5].
• Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry [6].
• Analysis of mutants of the chicken B cell line DT40 deficient in either Syk, Lyn, Btk, or PLC gamma 2 revealed that BCR-induced activation of PKC mu, like activation of PLC gamma 2, requires Syk and is partially regulated by Btk, but is Lyn independent [7].
• Syk, Pl3-K, PLC gamma 2, and Vav are constitutively tyrosine phosphorylated, and their tyrosine phosphorylation does not change following slg cross-linking [8].
• CD40 engagement also resulted in phosphorylation of phospholipase C gamma 2 of phosphatidylinositol (PLC gamma 2) and phosphatidylinositol (PI)-3-kinase [9].

Biological context of PLCG2

• To position the locus at a much finer resolution, PLCG2 sequences were amplified from a chromosome 16-specific somatic cell hybrid panel, which placed the gene on the long arm of the chromosome in band 16q24.1, a region that has few known genes [10].
• We also show that PLCG2 maps to the long arm of human chromosome 16, in the region q22-qter [11].
• A rodent/human somatic cell hybrid panel was used to map PLCG2 in the human genome [11].
• Wortmannin, another PtdIns 3-kinase inhibitor, also suppressed Epo-induced PLC-gamma2 tyrosine phosphorylation [12].
• Taken together, these results show that PtdIns 3-kinase controls Epo-induced GPI hydrolysis through PLC-gamma2 [12].

Anatomical context of PLCG2

• TPCK could suppress the induction of these two genes in either of Jurkat T cells and PBMCs, which might suggest the transcriptional regulation of PLCG2 and EPHX2 by NF-kappaB upon gamma-radiation [13].
• Among B-cell tumor lines, all five murine B-lymphoma lines tested and one of six human B-lymphoblastoid cell lines also expressed predominantly PLC-gamma 2 [14].
• PLC-gamma 2-specific antibodies were used to evaluate the distribution and potential signaling role of this isoform in lymphocytes [14].
• Several tyrosine-phosphorylated proteins were associated with the PLC gamma 2 precipitates from Mtb-stimulated neutrophils, of which pp46 was characterized as the Shc adapter protein [1].
• Phenylarsine oxide inhibits tyrosine phosphorylation of phospholipase C gamma 2 in human platelets and phospholipase C gamma 1 in NIH-3T3 fibroblasts [15].

Associations of PLCG2 with chemical compounds

• We have mapped the PLCG2 gene, which encodes the enzyme phosphatidyl inositol-specific phospholipase C-gamma 2 [10].
• We also present evidence that PLC-gamma2 translocation to the membrane fraction on Epo stimulation is completely inhibited by LY294002 [12].
• Signaling role for phospholipase C gamma 2 in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization. Involvement of a pathway distinct from FcR gamma chain and Fc gamma RIIA [16].
• Crude lysates that were prepared from bacteria that express PLCgamma2 were found to catalyze the hydrolysis of phosphatidylinositol 4,5 bisphosphate [2].
• Pretreatment with herbimycin A, a PTK inhibitor, blocked the Fc gamma R-induced tyrosine phosphorylation of PLC-gamma 1 and PLC-gamma 2, and the subsequent release of inositol phosphates [17].

Physical interactions of PLCG2

• Together, our results suggest a central role for the SH2(N) domain in directing PLC-gamma 2 into the close proximity of BCR signaling complex by its association with BLNK, whereby PLC-gamma 2 becomes tyrosine phosphorylated and thereby activated [18].

Enzymatic interactions of PLCG2

• Moreover Epo-activated Lyn phosphorylates in vitro PLC-gamma 2 immunoprecipitated from unstimulated cells [19].
• In addition, more recent data have indicated that PLC-gamma 2 is also capable of being tyrosine-phosphorylated in cells of hematopoietic origin, such as B cells and natural killer (NK) cells [20].
• In the present study we identified phospholipase C gamma 2 (PLC gamma 2) as one of the major proteins that was phosphorylated on tyrosine in response to beta 2 integrin activation [21].

Regulatory relationships of PLCG2

• B-cells rendered BTK-deficient by targeted disruption of the btk gene did not show enhanced PLC-gamma2 activation in response to EMF exposure [3].
• The enzyme activity and protein level of PLC-gamma 1 were markedly decreased in the human histiocytic leukemia U937 cell line during the differentiation process which is induced by phorbol 12-myristate 13-acetate (PMA) but those of PLC-gamma 2 were not altered [22].
• Here we report that PLC-gamma 2 expressed in a terminally-differentiated hematopoietic cell is also tyrosine-phosphorylated in response to an agonist [20].
• Integrin alpha IIb beta 3-dependent calcium signals regulate platelet-fibrinogen interactions under flow. Involvement of phospholipase C gamma 2 [23].
• This beta 2 integrin-induced phosphorylation of PLC gamma 2 occurred in parallel with an increased accumulation of Ins(1,4,5)P3 [21].

Other interactions of PLCG2

• In summary, this is the first report of a reconstitution of mammalian tyrosine kinase-linked effector activation in yeast cells and also the first demonstration of direct PLC gamma 2 activation by the proto-oncogene c-src [24].
• PLC activity in homogenates from hPLC-gamma 2 overexpressing cells was increased as compared to control cells transfected with the vector lacking the hPLC-gamma 2 cDNA insert [25].
• We conclude that both isoforms PLC-gamma 1 and PLC-gamma 2 are targets of the antigen receptor-associated protein tyrosine kinase [26].
• After labelling the cells with [35S]methionine an increase of radioactive label in a protein migrating at 148 kDa could be detected in IFN-alpha-stimulated, hPLC-gamma 2 overexpressing cells [25].
• A possible explanation for the SH2(N) requirement was provided by findings that this mutation abrogates the association of PLC-gamma 2 with an adaptor protein BLNK [18].

Analytical, diagnostic and therapeutic context of PLCG2

• We focused on two IR-related genes, phospholipase Cgamma2 (PLCG2) and cytosolic epoxide hydrolase (EPHX2), which were increased at 12 h after gamma-radiation in RT-PCR [13].
• Western blot analysis with anti(bovine PLC-gamma 2) antiserum showed increased hPLC-gamma 2 protein levels in hPLC-gamma 2 transfected cells [25].
• Northern blot analysis revealed an induction of hPLC-gamma 2 mRNA by interferon (IFN) alpha of about 25-fold as compared to the uninduced transcript level [25].
• Immunoblotting analyses with PLC-gamma 1- and PLC-gamma 2-specific antisera demonstrate that both isoforms are expressed in human NK cells [17].
• Receptor ligation triggers the activation of multiple receptor-associated src-family kinases leading to phosphorylation and activation of PLC gamma 1 and PLC gamma 2 [27].

References