Disease relevance of Plcg1

• In addition, exposure to pertussis toxin or exogenous activation of protein kinase A (PKA) inhibited PLC-gamma1 tyrosine phosphorylation in response to Ca(e) [1].
• Pathologically, plc-gamma1(-/-) chimeras showed multicystic kidney due to severe renal dysplasia and renal tube dilation [2].
• By screening a phage expression library using the monoclonal antibody (mAb) B16-5 which recognizes Src homology 3 (SH3) domains of phospholipase C-gamma and Nck, we have cloned a cDNA encoding the larger species of fyn mRNA [3].
• In this study, we examined the consequences of heat stress on epidermal-growth-factor (EGF)-induced receptor autophosphorylation and receptor-mediated tyrosine phosphorylation of phospholipase C-gamma 1 (PLC-gamma 1), a cellular substrate [4].
• PLC-gamma 1 with defective enzymatic activity was synthesized by substituting phenylalanine for histidine within the PLC-gamma 1 catalytic domain at amino acids 335 and 380, and mutant enzymes were expressed using a vaccinia expression system [5].

High impact information on Plcg1

• Although initial studies demonstrated a role for these proteins in TCR-mediated activation of phospholipase C-gamma, recent data indicate that Tec family kinases also regulate actin cytoskeletal reorganization and cellular adhesion following TCR stimulation [6].
• Moreover, recruitment of PLC-gamma to TrkA is essential for NGF-mediated potentiation of channel activity, and biochemical studies suggest that VR1 associates with this complex [7].
• Platelet-derived growth factor (PDGF) stimulates phospholipase C (PLC) activity and the phosphorylation of the gamma isozyme of PLC (PLC-gamma) in vitro and in living cells [8].
• The role of PLC-gamma in the phosphoinositide signaling pathway was addressed by examining the effect of overexpression of PLC-gamma on cellular responses to PDGF [8].
• Effect of phospholipase C-gamma overexpression on PDGF-induced second messengers and mitogenesis [8].

Chemical compound and disease context of Plcg1

• PLC-gamma activity and PLC-gamma protein content were decreased during the differentiation of F9 teratocarcinoma stem cells induced by a combination (RACT) of RA, dibutyryl cyclic AMP (C) and theophylline (T) [9].
• In the search for a substance which would specifically block a particular step in the signal transduction cascade, we identified glucopiericidin A produced by Streptomyces sp. as an inhibitor of phosphoinositide (PI)-turnover in phospholipase-Cgamma1 (PLC-gamma1) overexpressing NIH 3T3 fibroblasts (NIH 3T3gamma1) [10].

Biological context of Plcg1

• 0. Histological analysis indicates that Plcg1 (-/-) embryos appear normal at E 8.5 but fail to continue normal development and growth beyond E 8.5-E9 [11].
• An examination of carefully preserved wild-type embryos shows clear evidence of erythropoiesis, but erythropoiesis is not evident in Plcg1 nullizygous embryos at the same stage [12].
• On the contrary, treatment of Plcg1(-/-) cells with PKC-specific activator increased the Bcl-2 phosphorylation, decreased caspase-3 activity and improved their survival [13].
• Plcg2 does not map near its most closely related family member, Plcg1, in either genome, indicating that the mammalian Plcg genes belong to a dispersed family [14].
• By contrast, a receptor mutated in both the PI3K and PLC gamma association sites can still stimulate mast cell growth, indicating a crucial role of these effector molecules in regulating adhesion rather than cell growth [15].

Anatomical context of Plcg1

• Epidermal growth factor signaling and mitogenesis in Plcg1 null mouse embryonic fibroblasts [16].
• However, non-erythroid granulocyte/macrophage colonies are produced by Plcg1 null embryos [12].
• Activation of PKC was also markedly increased in both cell lines treated with H(2)O(2) (1-5 mM), but with low doses (50-200 microM), PKC activation was considerably decreased in Plcg1(-/-) cells [13].
• Kit signaling inhibits the sphingomyelin-ceramide pathway through PLC gamma 1: implication in stem cell factor radioprotective effect [17].
• In contrast, PLC alpha and PLC gamma 2 were abundantly expressed in all B cell lines tested [18].

Associations of Plcg1 with chemical compounds

• Our findings establish the significance of PLC gamma affinity for signal definition, the role of this receptor tyrosine kinase substrate as a negative feedback regulator and the importance of this regulatory function for mitogenesis and its disturbance in oncogenic aberrations [19].
• Relative to wild-type EGFR, the PLC gamma affinity increase of the EGFR switch mutant EGFR.X enhanced its inositol trisphosphate (IP3) and calcium signals and resulted in a more sustained mitogen-activated protein (MAP) kinase activation and accelerated receptor dephosphorylation [19].
• Specifically, 4 CRUs of AHNAK bind and activate PKC-alpha, which in turn stimulates the release of arachidonic acid near where PLC-gamma1 is localized [20].
• Integrin-dependent PLC-gamma1 phosphorylation mediates fibronectin-dependent adhesion [21].
• The soluble tyrosine kinase inhibitors, genistein (100 microM), herbimycin (10 microM) and geldanamycin (0.6 microM) which could affect signalling through PLC gamma hindered but never completely inhibited Ca2+ spiking in response to fertilization [22].

Physical interactions of Plcg1

• Transfection of dominant negative Src constructs into F4 cells had no effect on Grb2 binding or PLC gamma phosphorylation [23].
• Consistent with this prediction, autophosphorylated Syk efficiently binds the carboxyl terminal SH2 domain of phospholipase C-gamma 1 [24].
• The induction of PLC gamma-1 binding to dynamin occurs within minutes of the addition of platelet derived growth factor (PDGF) to cells [25].
• These data suggest that PLC gamma 1 constitutes a component in the cascade that couples sperm binding to the egg's extracellular matrix with acrosomal exocytosis, a regulated secretory response upon which fertilization depends absolutely [26].

Enzymatic interactions of Plcg1

• Furthermore, cleaved PLC-gamma1 could not be tyrosine-phosphorylated by EGFR in vitro [27].
• Furthermore, baculovirus-expressed Raf-1 phosphorylated purified PLC-gamma in vitro at sites which showed increased serine phosphorylation in vivo in response to PDGF [28].
• In contrast, PLC gamma and P13K were tyrosine phosphorylated after epidermal growth factor, but not calcium, stimulation [29].

Regulatory relationships of Plcg1

• Both Kit+ and KitA+ isoforms showed increased autophosphorylation and enhanced association with phosphatidylinositol (PI) 3' kinase and PLC gamma 1, when stimulated with recombinant soluble Steel factor [30].
• In addition, Plcg1 nullizygous embryos express a greatly reduced level of vascular endothelial growth factor receptor-2/Flk-1, consistent with significantly impaired vasculogenesis and erythropoiesis [12].
• Moreover, IL-1beta-induced association of PLC-gamma with SHPS-1 [31].
• These results indicate the existence of a novel signaling pathway where PLC-gamma activates Rac in a manner dependent on Iba1 [32].
• Furthermore, PD-98059 and U0126, two MAPK inhibitors, blocked PLC-gamma 1-induced expression of MDR1 [33].

Other interactions of Plcg1

• All the B cell lines tested expressed high levels of PLC alpha and PLC gamma 2 mRNA, whereas PLC beta and PLC delta mRNA expression were undetectable by both Northern blot and PCR analysis [18].
• Further analysis of these embryos demonstrates significantly diminished vasculogenesis in Plcg1 nullizygous embryos based on the lack of expression of the endothelial marker platelet endothelial cell adhesion molecule-1 [12].
• PLC-gamma1 is required for IGF-I protection from cell death induced by loss of extracellular matrix adhesion [34].
• Using a PCR-based strategy we have demonstrated that mouse oocytes have mRNA coding for PLC beta 1, PLC beta 3 and PLC gamma isoenzymes [22].
• Phospholipase C-gamma, protein kinase C and Ca2+/calmodulin-dependent protein kinase II are involved in platelet-derived growth factor-induced phosphorylation of Tiam1 [35].

Analytical, diagnostic and therapeutic context of Plcg1

• In contrast, PLC-gamma 1 was absent from the GV from the time of release from the follicle until 1 h later, and microinjection of anti-PLC-gamma 1 into the GV did not affect GVBD [36].
• PLC-gamma was immunoprecipitated, and associated proteins were characterized by autoradiography and Western blotting with anti-phosphotyrosine antibodies [37].
• Combinations of immunoprecipitation and immunoblotting with antibodies specific for proteins known to be associated with signaling pathways demonstrated that none of the major tyrosine-phosphorylated species correlated with phospholipase C-gamma 1, GTPase activating protein, or phosphatidylinositol 3' kinase [38].
• By pull-down of cell extract with the glutathione S-transferase (GST) fusion proteins with various domains of PLC-gamma1 followed by peptide sequence analysis, we identified EF-1alpha as a binding partner of a split PH domain of PLC-gamma1 [39].
• Phosphotyrosine site-directed antibodies revealed phosphorylation of PLC-gamma2, but not PLC-gamma1, upon integrin ligation by FN [40].

References