ABSTRACT
G-Protein-Coupled Receptor (GPCR)-Dependent ADAM-17 Regulated Ectodomain Shedding Stimulation of several GPCRs can promote EGFR activation and therefore its downstream signaling pathways (i.e. MAPK), a process known as GPCR-dependent EGFR transactivation (Daub et al. 1996). Th is cross-talk mechanism plays a central role in the ability of GPCRs to mediate proliferative signaling and its deregulation can induce pathological states such as cancer. In fact, it has been reported for several cancer types like head and neck, lung, breast, ovarian, prostate and in cancer cell lines (Filardo et al. 2000; Fischer et al. 2003; Lautrette et al. 2005; Yasuda et al. 2007; Bhola and Grandis 2008). GPCR-mediated EGFR transactivation is known to be a metalloproteinasedependent process. It is initiated by agonist-mediated stimulation of a GPCR that leads to the activation of a metalloproteinase, resulting in EGFR ligand shedding and subsequent activation of EGFR-downstream pathways (Prenzel et al. 1999). A wide variety of GPCR agonists can trigger EGFR transactivation, including thrombin, angiotensin II (ANGII), endothelin-1, bradykinin, lysophosphatidic acid (LPA), carbachol, dopamine and hormones (Dorsam and Gutkind 2007; Liebman 2011). Although diff erent ADAMs can regulate GPCR-mediated EGFR transactivation (Schäfer et al. 2004; Sanderson et al. 2006), ADAM17 seems to be the main protease involved, as it is the main protease involved in EGF ligand shedding (Ohtsu et al. 2006). Binding of an agonist to a GPCR induces a conformational change in the receptor and its associated heterotrimeric G proteins (a, b, g), ultimately leading to the dissociation of the GTP bound a subunit from the bg dimer (Choe et al. 2011). Both the a-GTP subunit and the bg dimers may play a role in EGFR transactivation (Sugden and Clerk 1997). For transactivation mediated by the a subunit, the Gq/11 family members stimulate the hydrolysis of the membrane phospholipid phosphatidylinositol-4, 5, bisphosphate (PtdInsP2) producing diacylglycerol (DG) and InsP3, which regulate PKC and intracellular Ca
2+ respectively, both known to play a role in ADAM17 activation. In this regard, it was demonstrated that ADAM17-dependent EGFR transactivation mediated by the ANGII receptors required Gq (Mifune et al. 2005; Ohtsu et al. 2008; Wang et al. 2009b). A similar mechanism and Gq requirement have been postulated for the P2Y6 receptor in response to g irradiation (Tamaishi et al. 2011). In addition, the Gi subunit has been implicated in the ADAM17-dependent EGFR transactivation by LPA in squamous cell carcinoma and breast cancer cells (Gschwind et al. 2003).
