Abstract
G protein-coupled receptors (GPCRs) represent the largest family of therapeutic targets for FDA approved drugs. Therefore, understanding the molecular regulation of their signaling pathways is of paramount importance. Similarly, the mitogen activated protein kinase (MAPK) p38 is a critical mediator of proinflammatory disease. Yet despite decades of intense investigation, therapeutically viable inhibitors have struggled to make it into the clinic. New studies describing the regulation and activation of a GPCR dependent atypical p38 signaling pathway represents a novel therapeutic avenue to the treatment of many proinflammatory disorders. These recent studies have defined how thrombin and ADP can induce Src dependent activation of the E3 ubiquitin ligase NEDD4-2. Src dependent phosphorylation of a 2,3-linker peptide releases NEDD4-2 auto-inhibition and triggers the induction of proinflammatory atypical p38 signaling from the endosome. Activation of the atypical p38 pathway requires the direct interaction between an adaptor protein TAB1 and p38, that bypasses the requirement for the classical MKK3/6 dependent activation of p38. Therefore, providing a mechanism to specifically block proinflammatory GPCR atypical p38 activation while leaving basic p38 activity intact. Critically, new studies demonstrated that disruption of the TAB1-p38 interface is a druggable target, that would enable the selective inhibition of proinflammatory p38 signaling and ischemic injury. Atypical p38 signaling is linked to multiple clinically relevant pathologies including inflammation, cardiotoxicity, myocardial ischemia and ischemia reperfusion injury. Therefore, GPCR induced endosomal p38 signaling represents a novel understudied branch of proinflammatory p38 signaling and an ideal potential therapeutic target that warrants further investigation.
Highlights
There are over 800 G protein–coupled receptors (GPCRs) expressed throughout the body, playing critical roles in many physiological functions ranging from the control of taste and sight to the regulation of neuronal function and inflammatory responses
A recent structural study showed that Ca2+ binding was essential for the active confirmation of NEDD4-2 and that the interaction between WW3 and the HECT domain requires partial unfolding of the HECT domain; suggesting that this mechanism regulates degradation of old or damaged E3 ligases (Escobedo et al, 2014)
The 2, 3-linker peptide wraps around the N-lobe and “locks” the C-lobe in the closed confirmation, by restricting movement of the flexible hinge loop (Zhu et al, 2017). Release of this inhibitory state was found to be regulated by binding of the NEDD4 family of interacting protein 1 (Ndfip1) or JNK1 mediated phosphorylation of the C-terminal proline rich region, both of which have been shown to occur in activated Tcells (Gao et al, 2004; Gallagher et al, 2006; Oberst et al, 2007)
Summary
There are over 800 G protein–coupled receptors (GPCRs) expressed throughout the body, playing critical roles in many physiological functions ranging from the control of taste and sight to the regulation of neuronal function and inflammatory responses. In addition to the well-documented role of ubiquitination and NEDD4 ligases in the regulation of subcellular trafficking they can regulate GPCR induced signaling (Abagyan and Totrov, 1994; Marchese and Benovic, 2001; Tanowitz and Von Zastrow, 2002; Marchese et al, 2003; Bhandari et al, 2007; Oo et al, 2007, 2011; Wolfe et al, 2007; Shenoy et al, 2008, 2009; Berthouze et al, 2009; Hislop et al, 2009; Mines et al, 2009; Berlin et al, 2010; Malik and Marchese, 2010; Chen et al, 2011; Groer et al, 2011; He et al, 2011; Henry et al, 2011, 2012; Dores et al, 2012, 2015; Grimsey et al, 2015, 2018; Jean-Charles et al, 2016) (Table 1).
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