Engagement of β-arrestin by transactivated insulin-like growth factor receptor is needed for V2 vasopressin receptor-stimulated ERK1/2 activation

Abstract

G protein-coupled receptors (GPCRs) have been shown to activate the mitogen-activated protein kinases, ERK1/2, through both G protein-dependent and -independent mechanisms. Here, we describe a G protein-independent mechanism that unravels an unanticipated role for β-arrestins. Stimulation of the V2 vasopressin receptor (V2R) in cultured cells or in vivo in rat kidney medullar collecting ducts led to the activation of ERK1/2 through the metalloproteinase-mediated shedding of a factor activating the insulin-like growth factor receptor (IGFR). This process was found to be both Src- and β-arrestin–dependent. Whereas Src was found to act upstream of the metalloproteinase activation and be required for the release of the IGFR-activating factor, β-arrestins were found to act downstream of the IGFR transactivation. Unexpectedly, the engagement of β-arrestins by the IGFR but not by the V2R was needed to promote the vasopressin-stimulated ERK1/2 activation, indicating that a pool of β-arrestins distinct from those β-arrestins recruited to the V2R acts downstream of the receptor tyrosine kinase to activate ERK1/2. Such a dual site of action for β-arrestins helps explain the pleiotropic actions of this scaffolding protein. Given the role that V2R-stimulated ERK1/2 plays in kidney cell proliferation, this transactivation mechanism may have important implications for renal pathophysiology. Still, the role of β-arrestins downstream of a transactivation event is not limited to the V2R, because we observed a similar involvement for an unrelated GPCR (the platelet-activating factor receptor), indicating that it may be a general mechanism shared among GPCRs.

Vasopressin-2 Receptor Signaling and Autosomal Dominant Polycystic Kidney Disease

“…58 These data are consistent with studies in undifferentiated human embryonic kidney cells expressing transfected V2R. 59 ERK activation is known to be a key player in proliferating epithelia. 56 Most importantly, basal cAMP levels are not elevated in rodent models of ADPKD.…”

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

“…In contrast, others have suggested alternate mechanisms for ROS-dependent transactivation signalling such as intracellular kinases or direct interactions between the GPCR and PTKR by proteolysis of regulatory proteins inhibiting PTKR activity (Finkel 2000). Whilst transactivation of EGFR is the most well-known, transactivation of other PTKR such as PDGF, fibroblast growth factor, insulin like growth factor 1 and Trk exist (Oligny-Longpre et al 2012;Tsai et al 2014;Puehringer et al 2013). Although the importance of GPCR mediated transactivation of the EGFR is established, the mechanism is still unclear and studies are continuing.…”

The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors

“…Although downstream effects are believed to be mediated in part by activation of PKA, other kinases, such as PKB, are likely to play an important role (94). Myosin light chain kinase is also activated and required for AQP2 trafficking (22), and calmodulin-dependent kinases are activated in response to V2Rs (23), whereas multiple MAPKs are inactivated in response to V2R occupation (21,91). It has also been demonstrated that AQP2 can be phosphorylated at Ser 256 by multiple protein kinases (30).…”