Transactivation of Epidermal Growth Factor Receptor by G Protein-Coupled Receptors: Recent Progress, Challenges and Future Research

Abstract

Both G protein-coupled receptors (GPCRs) and receptor-tyrosine kinases (RTKs) regulate large signaling networks, control multiple cell functions and are implicated in many diseases including various cancers. Both of them are also the top therapeutic targets for disease treatment. The discovery of the cross-talk between GPCRs and RTKs connects these two vast signaling networks and complicates the already complicated signaling networks that regulate cell signaling and function. In this review, we focus on the transactivation of epidermal growth factor receptor (EGFR), a subfamily of RTKs, by GPCRs. Since the first report of EGFR transactivation by GPCR, significant progress has been made including the elucidation of the mechanisms underlying the transactivation. Here, we first provide a basic picture for GPCR, EGFR and EGFR transactivation by GPCR. We then discuss the progress made in the last five years and finally provided our view of the future challenge and future researches needed to overcome these challenges.

Keywords: EGF receptor; G protein-coupled receptors; cancer; mechanisms.

Figure 1

Schematic illustration of EGFR transactivation by GPCR. Two mechanisms have been proposed and supported by the available data: TMPS and ligand-independent intracellular pathways. (A) TMPS: In this model, GPCR-induced EGFR transactivation depends on the activation of MMPs that are able to cleave EGFR ligands such as HB-EGF and stimulate ligand shedding. The ligands released into the extracellular space then bind to EGFR and stimulate the dimerization and activation of the receptors, which leads to the activation of signaling cascades; (B) Ligand-independent pathway: This pathway involves the activation of intracellular protein tyrosine kinases (PTKs) such as Src family proteins. Src phosphorylates the tyrosines residues in the cytosolic domain of EGFR. The phosphorylated EGFR is able to interact with downstream signaling proteins, leading to the activation of various signaling pathways. Src could be activated by GPCR through different mechanisms; (C) Future research: Future research should focus on the EGFR transactivation through ligand-independent Src pathway. It is important to determine how Src activates EGFR, the activation status of Src-activated EGFR, and the effects of Src-activated EGFR on the downstream signaling cascades and cell functions. For example, does Src stimulates the dimerization of EGFR? Does Src phosphorylate all the major phosphor tyrosine (Y) residues of EGFR? What are the downstream signaling pathways activated and what is the physiological consequence of this activation?