G Protein-Coupled Receptors-Induced Activation of Extracellular Signal-Regulated Protein Kinase (ERK) and Sodium-Proton Exchanger Type 1 (NHE1)

Abstract

G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface molecules, involved in signal transmission, accounting for >2% of the total genes encoded by the human genome. GPCRs have been linked to key physiological functions, including immune responses, cardiacand smooth-muscle contraction and blood pressure regulation, neurotransmission, hormone and enzyme release from endocrine and exocrine glands. Thus, GPCRs contribute to embryogenesis, tissue remodelling and repair, inflammation, angiogenesis and normal cell growth. Their dysfunction contributes to multiple human diseases, and GPCRs represent the target of over 50% of all current therapeutic agents (Reviewed by Pierce et al., 2002). In addition, recent studies indicate that many GPCRs are overexpressed in various cancer types, and contribute to tumor cell growth when activated by circulating or locally produced ligands, suggesting a crucial role of GPCRs in cancer progression and metastasis. For example, many potent mitogens such as thrombin, lysophosphatidic acid (LPA), endothelin and prostaglandins stimulate cell proliferation by acting on their cognate GPCRs in various cell types. (Reviewed by Dorsam & Gutkind, 2007). The mechanisms that control cellular proliferation are important in normal physiology and disease states. Multiple mitogens that activate GPCRs stimulate the extracellular signal-regulated protein kinase (ERK) and lead to proliferation of mammalian cells. Another extensively studied mitogenic effector pathway in addition to ERK that ultimately leads to cell proliferation, is the ubiquitous plasma membrane sodium-proton exchanger type 1 (NHE1). NHE1 and ERK have both been implicated as key mediators of growth signals (Noel & Pouyssegur, 1995; Rozengurt, 1986; Kapus et al, 1994; Krump et al, 1997), therefore the regulatory relationships between NHE1 and ERK have been the subject of a number of studies over the last decade. Because both proteins can serve mitogenic functions, and because both are activated by similar stimuli, it has been hypothesized that