Heterotrimeric G Proteins Directly Regulate MMP14/Membrane Type-1 Matrix Metalloprotease

Abstract

Background: Mechanisms underlying GPCR-mediated EGFR transactivation are not fully defined. Results: Heterotrimeric G proteins directly regulate membrane-localized MMP14/MT1-MMP, resulting in HB-EGF release and EGFR transactivation. Conclusion: These results define a previously unrecognized, membrane-delimited mechanism for EGFR transactivation. Significance: This mechanism likely plays a role in settings that involve GPCR-RTK transactivation and may represent new therapeutic opportunities.

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

“…Metalloproteases shedding mature EGFR ligands may also be a direct target of G proteins, as revealed in the recent study of Overland & Insel (2015).…”

“…In addition to conventional G protein-dependent induction of EGFR ligand shedding, MMPs can function as direct G protein effector molecules: Overland and Insel (2015) have identified a novel path of EGFR transactivation in which MMP14 acts as a direct heterotrimeric G protein effector, activated by G (potentially G) to trigger HB-EGF release. Other studies identify G protein independent/β-arrestin dependent mechanisms of EGFR activation (Tilley, 2011).…”

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

“…This ligand-dependent mechanism involves several MMPs, including MMP-1 MMP-2, MMP-7, MMP-9 and MMP-14 and has been shown to be involved in GPCR mediated transactivation of multiple PTKRs such as EGFR, vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) (Overland and Insel 2015;Ancha et al 2007;Carbajal et al 2011;Hao et al 2004). In rat mesenteric arteries, phenylephrine stimulated EGFR transactivation was dependent on MMP-7 as the response was blocked by the MMP inhibitor GM6001 as well as MMP-7 specific antibodies.…”

Membrane-anchored proteases in endothelial cell biology

“…Agonists of multiple G protein-coupled receptors (GPCR) can activate ADAMs to produce mature EGFR ligands that lead to EGFR transactivation; signaling events that may require trafficking and compartmentalization of the GPCR and ADAM providing the temporal and spatial regulation necessary for rapid and specific signal activation [84]. Further, a recent report indicates that heterotrimeric G-proteins may also directly activate membrane tethered proteases in a membrane delimited manner [85*]. MT1-MMP was shown to be activated via a direct binding interaction with activated G-protein βγ subunits, resulting in HB-EGF release and EGFR transactivation [85*].…”

“…Further, a recent report indicates that heterotrimeric G-proteins may also directly activate membrane tethered proteases in a membrane delimited manner [85*]. MT1-MMP was shown to be activated via a direct binding interaction with activated G-protein βγ subunits, resulting in HB-EGF release and EGFR transactivation [85*]. It remains to be determined whether other membrane-anchored proteases may be activated by the same or different G-proteins in a similarly direct manner.…”