Novel molecular signaling platform regulating receptor activation and cell function

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Molecular-targeted G-protein-coupled receptor (GPCR) signaling in human disease has become an important area to scientific and medical professionals. I am studying GPCR signaling because my research program has discovered an entirely new GPCR signaling platform. The interactions between GPCRs with their large number of different G-protein subunits and glycosylated receptors involved in all cells of our body are quite diverse. A vast array of stimuli is capable of eliciting conformational changes in these receptors. They are activated by many ligands, both internal within the body, such as hormones and neurotransmitters, and external light, odorants, and others. One GPCR is capable of initiating multifunctional signaling which may potentiate an amplification of the response produced by separate circumstantial signals within the cell. This cross-talk among different GPCR transduction signals is a focus of intense research in the world. My HQPs and I have uncovered the invisible link connecting ligand-binding and receptor activation to a novel GPCR-signaling platform. This molecular organizational GPCR-signaling platform potentiates Neu1 sialidase and matrix metalloproteinase-9 (MMP-9) enzyme cross-talk on growth factor and pathogen-sensing TOLL-like receptors (TLRs) to facilitate receptor association and cellular signaling. The process involves ligand binding to receptors to initiate a conformational change to potentiate GPCR-signaling and MMP-9 activation to induce Neu1. Activated Neu1 specifically hydrolyzes a-2,3-sialyl residues on receptors, the structural perturbation of which triggers dimeric receptor complex formation and subsequent activation. Collectively, this evidence supports a new role for Neu1 and MMP9 enzymes in the activation of glycosylated receptors through yet an undefined mechanism(s). The long term objective is to increase our comprehension at the molecular and genetic levels of the new role for the Neu1-MMP9 crosstalk in alliance with a functional GPCR-signaling complex in controlling receptor activation. We are convinced that our study will provide the first demonstration for this new GPCR signaling platform as a potential signal transducing mechanism for receptors in cellular responses to stimuli. Since several cell-expressed GPCRs have been identified and targeted with therapeutic intent in human diseases involving infectious disease to cancer, studies about the key players potentiating GPCR-signaling to activate MMP-9 and Neu1 would radically redefine the current dogma(s) governing the mechanism of the cross talk between GPCR and cellular responses to stimuli. Targeting the molecular GPCR-signaling platform tethered to growth factor and pathogen-sensing receptors may provide important biological approaches to disease-intervention strategies and to benefit Canadians.