Transactivation joins multiple tracks to the ERK/MAPK cascade

Abstract

Many agonists of G-protein-coupled receptors (GPCRs) can stimulate receptor tyrosine kinases and the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. A 'transactivation' mechanism, which links these events in one signalling chain, inspired many researchers, but inevitably raised new questions. A 'multi-track' model for GPCR signalling to the ERK/MAPK pathway might resolve some of the puzzles in the transactivation field.

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…Activation of the small GTPase Rac also promotes membrane recruitment of NADPH oxidase complex components (Gregg et al, 2003), while the p47phox subunit (necessary for oxidase activation) is phospho-regulated by both PKC (Fontayne et al, 2002) and the PI3K/Akt pathways (Hoyal et al, 2003). Generation of ROS plays a key role in MMP activation (Wetzker and Bohmer, 2003), increases PTK activity and EGFR phosphorylation via inhibitory oxidation of tyrosine phosphatases targeting Src kinase and EGFR (Salmeen et al, 2003;Chen et al, 2006), and may enhance proteolysis of proteins that repress PTK activity (Liebmann, 2011;George et al, 2013a). These important functions may, in turn, render EGFR transactivation sensitive to age-and disease-dependent perturbations in myocardial ROS and phosphatases.…”

“…In terms of cardiac protection via GPCR agonism/ischaemic preconditioning, ROS generation (via NADPH oxidase activity, mitochondrial electron transport chain) has been localised both up-and downstream of mitochondrial KATP channels and PKC (Hausenloy and Yellon, 2006;Murphy and Steenbergen, 2008;Heusch, 2015). However, ROS are also important in MMP activation and EGFR ligand shedding (Wetzker and Bohmer, 2003). In cardiac fibroblasts, for example, ROS are localised upstream of MMP-dependent HB-EGF shedding (in transactivation via endothelin-1), facilitating HB-EGF activation of EGFR via inhibitory oxidation of Src homology 2-containing tyrosine phosphatase (Chen et al, 2006).…”

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

“…PI3K/Akt signaling is initiated by activation of receptor tyrosine kinases or G protein-coupled receptors (Wetzker and Bohmer, 2003). Activation involves PI3K recruitment to the receptor involving PI3K's Src homology domains and/or Src-type kinase action.…”

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

“…While EGF is not detected after injury (Yang et al, 2004), release of heparin binding epidermal-like growth factor (HB-EGF) has been detected in the extracellular matrix during development or injury in a number of cell types (Xu et al, 2004;Prenzel et al, 1999;Prenzel et al, 2000;Wetzker and Bohmer, 2003;Gschwind et al, 2001;Fischer et al, 2004). Furthermore, stimulation of GPCRs can cause activation of metalloproteases leading to cleavage of pro-HB-EGF on the cell surface (Prenzel et al, 2000;Wetzker and Bohmer, 2003). In addition, P2Y receptors have been shown to recruit Src for induction of downstream signaling events such as activation of EGFR (Liu et al, 2004).…”