Marcin Maziarz

I joined the lab of Mikel Garcia-Marcos in December 2016, with a particular interest in studying the regulation of heterotrimeric G proteins, as well as their role in disease. For one of my projects, I have been examining the link between G protein mutations and cancer. In particular, the Gαq/11 proteins are mutated in nearly 90% of patients suffering from an eye cancer known as uveal melanoma (UM), and which lacks effective therapies. For this reason, it is critical that we understand the molecular mechanisms that are dysregulated in this cancer. In a 2018 publication in the Journal of Biological Chemistry (JBC), we describe how the Gαq Q209P mutant protein frequently found in UM has distinct molecular properties from other Gαq mutant proteins and from the normal protein. In the future, we hope to take advantage of these properties to develop specific inhibitors of this mutant protein that do not affect the normal Gαq protein, which could pave the way for therapies for this cancer type.

In addition to activation by G-protein coupled receptors (GPCRs), G proteins are also activated by cytoplasmic factors, called non-receptor GEFs. Dysregulation of these proteins has been linked to human disorders, including cancer, birth defects, heptic fibrosis, or kidney failure, among others. Identifying additional activators using strictly bioinformatics approaches has been challenging, as only a subset of these proteins have a short Gα-binding-and-activating (GBA) motif in common, necessitating a more rigorous approach. In a 2018 JBC Editors’ Pick study, we outline a pipeline for the discovery and validation of non-receptor GBA proteins, and identify a new member called PLCδ4b. Using a combination of biochemical and genetic assays, we show that PLCδ4b has all of the characteristics of the known non-receptor GBA proteins: it binds to the inactive Gαi protein, promotes nucleotide exchange in vitro, and activates G protein signaling in cells.

Considering the crucial role of G proteins and GPCRs in human pathophysiology, there is a major need in the biomedical community for improved tools to study G protein signaling. One major limitation of current reporters is that they require overexpression of G proteins and their coupled receptors, which may not be physiologically relevant, and/or overexpression of multiple genetic components, which is difficult to achieve in some cells. To overcome these problems, I am currently developing G protein activity biosensors that can more faithfully report G protein activation, and can be implemented to monitor the activation of endogenous G proteins in their native cellular context.