Disease relevance of PLCB3

• Differential expression of these genes may contribute to the PLCB3-induced tumor suppression of neuroendocrine tumor cell lines [1].
• RESULTS: We show that the PLCB3 transcript is missing in 8 out of 14 MEN1-associated neoplasias as well as in 4 out of 10 bronchial carcinoids, 2 out of 10 exocrine pancreatic cancers and one sporadic adrenocortical carcinoma [2].
• 7. PLC beta 3 activity, measured with pertussis pretreated membranes, showed a dose-dependent increase in the presence of p[NH]ppG or guanosine 5'-[gamma-thio]triphosphate (GTP[S]) [3].
• Exclusion of the phosphoinositide-specific phospholipase C beta 3 (PLCB3) gene as a candidate for multiple endocrine neoplasia type 1 [4].

High impact information on PLCB3

• Based on the in vitro effects of PI-TP, we surmise that it is involved in transporting PI from intracellular compartments for conversion to PI bisphosphate (PIP2) prior to hydrolysis by PLC-beta 2/PLC-beta 3, the endogenous PLC isoforms present in these cells [5].
• The best characterized of the intranuclear lipids are the inositol lipids that form the components of a phosphoinositide-phospholipase C cycle [6].
• The increases in both motility and calpain activity by IP-9 were blocked by pharmacological and molecular inhibition of phospholipase C-beta3 and chelation of calcium, which prevented an intracellular calcium flux [7].
• NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation [8].
• Consistently, LPA(2)-mediated PLC-beta activation was specifically inhibited by the gene silencing of PLC-beta3 [8].

Biological context of PLCB3

• Localization of the human phosphatidylinositol-specific phospholipase c beta 3 gene (PLCB3) within chromosome band 11q13 [9].
• PLCB3 plays an important role in signal transduction and, moreover, shows loss of expression in some endocrine tumors, in accordance with a putative tumor suppressor gene function, and thus appears to be an excellent candidate for MEN1 [4].
• PLCB3 transfection resulted in increased expression of 4 genes and decreased of 2 [1].
• BACKGROUND: Phospholipase C beta 3 (PLCB3) plays an important role in the signal transduction of the seven transmembrane receptors [2].
• Transfection of PLCB3 to neuroendocrine cell lines lacking expression suppresses the neoplastic phenotype and affects the gene expression of S100A3 and human mismatch repair protein, suggesting a role for PLCB3 in neuroendocrine tumorigenesis [2].

Anatomical context of PLCB3

• Transfection of PLCB3 to neuroendocrine cell lines induces growth suppression and phenotypic alterations, but the mechanisms remain unclear [1].
• To investigate the underlying events behind this tumor suppression, we performed an RT-Differential cDNA Display of total RNA from BON-1 (human endocrine pancreatic tumor cell line) transfected with PLCB3 and compared to wild type and BON-1 transfected with vector without insert [1].
• Reverse transcriptions and polymerase chain reactions (RT-PCR) provided evidence for PLC beta 1 mRNA being expressed in human myocardium, whereas PCR products corresponding to PLC beta 2 and PLC beta 3 mRNAs were not detected [10].
• In 31 parathyroid glands from 17 patients with MEN 1, CAS distribution was studied immunohistochemically and parallel sections were explored for PLC beta 3 mRNA expression by in situ hybridization [11].
• Neither of the receptors can activate endogenous PLC beta3 or recombinant PLC beta3 in transfected COS-7 cells [12].

Associations of PLCB3 with chemical compounds

• Genomic organization and complete cDNA sequence of the human phosphoinositide-specific phospholipase C beta 3 gene (PLCB3) [13].
• Furthermore, mutation of these serine residues removed the inhibitory effect of PKG on the activation of the mutant PLC-beta3 proteins by G-protein subunits [14].
• A time- and DPDPE concentration-dependent and naloxone-reversible increase in the PLC-beta3 phosphorylation can be demonstrated [15].
• Furthermore, the LPA- and DPDPE-mediated PLC-beta3 phosphorylation was additive and was much less than that observed with phorbol-12-myristate-13-acetate [15].
• This PLC-beta3 phosphorylation was mainly due to PKC activation because pretreatment of NG108-15 cells with calphostin C could block the DPDPE effect [15].

Physical interactions of PLCB3

• Furthermore, PLC-beta3 interacted with NHERF2 rather than with other PDZ-containing proteins [16].
• Identification of a region at the N-terminus of phospholipase C-beta 3 that interacts with G protein beta gamma subunits [17].

Regulatory relationships of PLCB3

• We demonstrate that PKC rather than protein kinase A mediates the G protein-coupled receptor-induced phosphorylation of PLC-beta3 [18].
• Phosphorylation and regulation of G-protein-activated phospholipase C-beta 3 by cGMP-dependent protein kinases [14].
• The cleavage of these PLC-beta 3 enzymes was completely blocked by calpain inhibitor, calpeptin, indicating that the PLC-beta 3 modification may be a consequence of platelet activation leading to activation of calpain [19].

Other interactions of PLCB3

• We can now exclude PLCB3 from candidacy as the MEN1 gene [4].
• Using its second PDZ domain, NHERF2 was found to indirectly link LPA(2) to PLC-beta3 to form a complex, and the other PLC-beta isozymes were not included in the protein complex [8].
• Immunoprecipitation studies revealed that NHERF2 interacts specifically with PLC-beta3, but not with other PLC-beta isotypes [16].
• Regulation of phospholipase C-beta 3 activity by Na+/H+ exchanger regulatory factor 2 [16].
• Further assessment of homodimerization status by coimmunoprecipitation assays with differentially tagged PLC-beta3 fragments demonstrated that at least two subdomains of PLC-beta3 are involved in dimer formation, one in the catalytic X and Y domains and the other in the G protein-regulated carboxyl-terminal domain [20].

Analytical, diagnostic and therapeutic context of PLCB3

• Since we considered PLCB3 a candidate gene for these EGCTs, we set out to clone the PLCB3 cDNA, from which the 5' end was still missing, and performed Northern and Southern blot analyses [9].
• Size-exclusion chromatography data suggest that PLC-beta3 and PLC-beta1 form higher affinity homodimers than PLC-beta2 [20].
• By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)) [14].
• Molecular cloning and characterization of a cDNA encoding mouse phospholipase C-beta3 [21].
• Immunoprecipitation with antibodies directed against phospholipase C-beta3, -gamma1, or -gamma2 isoforms (which have molecular weights around 150 kDa) followed by Western blotting using an anti-phosphotyrosine antibody showed that only phospholipase C-gamma1 and -gamma2 were phosphorylated [22].

References