Phospholipase C-ϵ Augments Epidermal Growth Factor-dependent Cell Growth by Inhibiting Epidermal Growth Factor Receptor Down-regulation

Abstract

The down-regulation of the epidermal growth factor (EGF) receptor is critical for the termination of EGF-dependent signaling, and the dysregulation of this process can lead to oncogenesis. In the present study, we suggest a novel mechanism for the regulation of EGF receptor down-regulation by phospholipase C-⑀. The overexpression of PLC-⑀ led to an increase in receptor recycling and decreased the down-regulation of the EGF receptor in COS-7 cells. Adaptor protein complex 2 (AP2) was identified as a novel binding protein that associates with the PLC-⑀ RA2 domain independently of Ras. The interaction of PLC-⑀ with AP2 was responsible for the suppression of EGF receptor down-regulation, since a perturbation in this interaction abolished this effect. Enhanced EGF receptor stability by PLC-⑀ led to the potentiation of EGF-dependent growth in COS-7 cells. Finally, the knockdown of PLC-⑀ in mouse embryo fibroblast cells elicited a severe defect in EGF-dependent growth. Our results indicated that PLC-⑀ could promote EGF-dependent cell growth by suppressing receptor down-regulation.

Potentially Functional Variants of PLCE1 Identified by GWASs Contribute to Gastric Adenocarcinoma Susceptibility in an Eastern Chinese Population

“…These structural features suggest that PLCE1 is regulated downstream of the Ras superfamily GTPases [25], [26]. PLCE1 catalyzes the hydrolysis of polyphosphoinositides into two intracellular second messengers, such as inositol-1,4,5 trisphosphate (IP 3 ) and diacylglycerol (DAG) that are involved in calcium mobilization and protein kinase C activation, respectively [25], [27]. Therefore, PLCE1 acts as an effector of the Ras family small GTPases and thus plays an important role in regulating cell growth, differentiation and development.…”

“…Two RA domains located at the carboxyl terminus of PLCE1 are associated with H-Ras and Rap1A in a GTP-dependent manner. These structural features suggest that PLCE1 is regulated downstream of the Ras superfamily GTPases [25], [26]. PLCE1 catalyzes the hydrolysis of polyphosphoinositides into two intracellular second messengers, such as inositol-1,4,5 trisphosphate (IP 3 ) and diacylglycerol (DAG) that are involved in calcium mobilization and protein kinase C activation, respectively [25], [27].…”

Multiple roles of phosphoinositide-specific phospholipase C isozymes

“…In that report, GEF activity of PLC-ε was required for the Erk activation and cell astrocyte proliferation. In addi-http://bmbreports.org BMB reports tion, PLC-ε promotes EGF-dependent cell growth by inhibition of EGF receptor downregulation (206). Taken together, PLC-ε seems to promote cell growth contributing to the normal developmental processes or tumor formation.…”

“…In addition, it was evidenced that PLC-ε plays a role in agonist-dependent proliferation. PLC-ε induced PDGF-dependent cell growth in BaF3 cells overexpressing PDGF receptor (198) or EGF-dependent cell growth in HEK293 cells or MEF cells (197,206). A recent report indicates that thrombin-dependent astrocyte proliferation is mediated by PLC-ε (207).…”

Knockdown of Phospholipase C-Epsilon by Short-Hairpin RNA-Mediated Gene Silencing Induces Apoptosis in Human Bladder Cancer Cell Lines

“…It has been reported that PLCe involved in skin tumor 20 and head and neck squamous cell carcinoma development. 11 Furthermore, PLCe could inhibit epidermal growth factor receptor (EGFR) downregulation, 21 and this process may induce an abnormal increase of EGFR, which may lead to oncogenesis. On the basis of such findings, we propose that there exists a previously unrecognized role for PLCe as an important factor involved in regulating bladder cancer progression.…”