Jingyi Zhao, Ph.D (Garcia-Marcos Lab) awarded 2022 Dahod International Scholar

Congratulations to Jingyi Zhao, Ph.D. (Garcia-Marcos Lab) who was awarded 2022 Dahod International Scholar.

Jingyi, a postdoc in Dr. Mikel Garcia-Marcos’ laboratory, will characterize a small molecule inhibitor of a novel signaling mechanism that promotes breast cancer metastasis. He has identified a promising candidate molecule, named IGGi-11, that disrupts a protein signaling complex specifically present in metastatic cancer cells. He intends to further confirm the specificity of this molecule in preventing cancer cell invasiveness without overt cytotoxic effects in normal cells, and to work towards developing analog compounds with improved properties in preclinical breast cancer models.

Remi Janicot awarded American Heart Association fellowship

Remi Janicot in the Garcia-Marcos laboratory was awarded an American Heart Association (AHA) predoctoral fellowship for his project "Optical biosensor platforms for the direct interrogation of GPCR signaling in cardiovascular cells”

The goal of this project is to create new experimental tools that can transform how GPCRs are studied. The main benefit over current methods is that these tools can be easily used in cell models that are relevant to study heart or lung disease, which has been an important limitation in the field. These new experimental possibilities would open new doors for the entire cardiovascular research community. The tools designed in this project will allow to study GPCRs with fidelity and precision. This would pave the way to develop new drugs to treat life-threatening cardiac disorders.

Congratulations Remi!

 

Mikel Garcia-Marcos receives John Abel Award from ASPET

Congratulations to Dr. Mikel Garcia-Marcos for receiving the 2022 American Society for Pharmacology and Experimental Therapeutics (ASPET) John J. Abel Award in Pharmacology. The Abel Award is named after the founder of ASPET. It was established in 1946 to stimulate fundamental research in pharmacology and experimental therapeutics by young investigators.

The award will be presented at the ASPET Business Meeting and Awards Presentation during the ASPET Annual Meeting at Experimental Biology 2022 on Saturday, April 2 at 4:30 pm in Philadelphia. Additionally, Dr. Garcia-Marcos will deliver the Abel Award Lecture titled The Secret Life of G Proteins to open the 2022 annual meeting on Saturday, April 2 at 10:00 am in Philadelphia.

Research News: New Discovery from the Garcia-Marcos Laboratory

The Garcia-Marcos laboratory has discovered that heterotrimeric G-proteins, which are critical molecular switches in cellular communication processes, can trigger different responses in cells depending on the type of protein that activates them.

Heterotrimeric G-proteins are typically activated by G-protein-coupled receptors (GPCRs), which are the target for over one-third of drugs approved for use in the clinic. But G-proteins can also be activated by other proteins that are not GPCRs, a mechanism with important implications for human physiology and disease. The Garcia-Marcos laboratory has used an innovative approach to dissect and compare the consequences of G-protein stimulation by different activators, including GPCRs and various non-GPCR proteins. The approach leveraged a recently developed type of biosensors capable of detecting different forms of active G-proteins in living cells in real time. These were combined with engineered G-protein activator constructs that could be turned on at will with an exogenous synthetic chemical.

The main conclusion is that, contrary to previous beliefs, GPCR and non-GPCR activators elicit different forms of G-protein activation in cells. These findings have important implications in our understanding of pharmacologically actionable signaling hubs in cells, which could be leveraged to envision and design new therapeutic agents.

You can read the article here:

Garcia-Marcos M. Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators. Elife. 2021 Mar 31;10:e65620. PMID: 33787494 https://pubmed.ncbi.nlm.nih.gov/33787494/

Research discoveries: seeing G-protein signaling

The Garcia-Marcos lab has developed a suite of modular optical biosensors that enables detection of hetrotrimeric G-protein activity in live cells in contexts ranging from tumor cells to primary neurons.
 
Heterotrimeric G-proteins are the main transducers of signals from GPCRs, mediating the action of countless natural stimuli and therapeutic agents (about one-third of FDA-approved drugs). The new biosensors described in the paper published in Cell allow the direct detection of endogenous active G-proteins, something that had not been possible to date. This work showcases several biosensors for different G-protein subtypes and applications in multiple cellular models and research areas, from characterizing cancer-associated G-protein mutants to neurotransmitter signaling in primary neurons. This new resource will be valuable in characterizing G-protein signaling in live cells with high fidelity, temporal resolution, and convenience, propelling both fundamental research and drug discovery applications.

New research discoveries: Regulators of G protein signaling in cancer

The Garcia-Marcos laboratory has recently published a new study in the journal Science Signaling. In this study, the authors characterized how cancer-associated mutations in a family of negative regulators of G proteins affect the ability of these regulators to modulate G protein activity. Many of these mutations turn out to be deleterious for the G protein regulatory function. In the words of the journal's Editor:

"Mutations in the genes encoding the α subunits of heterotrimeric G proteins are associated with cancer. In particular, mutations that prevent the Gα subunits from hydrolyzing GTP, thus rendering them constitutively active, are pro-oncogenic. DiGiacomo et al. surveyed cancer-associated mutations in regulator of G protein signaling (RGS) proteins, which are physiological inhibitors of G proteins. Through bioinformatics analysis, genetic interaction studies in yeast, and functional assays in mammalian cells, the authors showed that many cancer-associated RGS mutants fail to inhibit G protein signaling because of reduced protein stability or impaired interactions with their targets. With these tools, further cancer-associated mutations in RGS proteins can be characterized."

This work was spearheaded by the former Garcia-Marcos' laboratory postdoc Vincent DiGiacomo, who is currently working in the Cambridge biotech company DeepBiome, with the help of other laboratory members, including two undergraduate students from Boston University. The entire study was carried out in the Department of Biochemistry.

Research Discoveries: New ways of activating G-proteins during embryonic development

Heterotrimeric G proteins are signaling switches that control cellular communication across metazoans. From a traditional standpoint, these G-proteins are activated by G-protein-coupled receptors (GPCRs). However, a recent paper published in the Journal of Cell Biology by Arthur Marivin and colleagues provides direct evidence that heterotrimeric G-proteins can be activated in vivo by a cytoplasmic factor instead of by a GPCR. Specifically, DAPLE, a non-receptor protein bearing an evolutionarily conserved G-protein activating motif, triggers apical cell constriction during neurulation in Xenopus and zebrafish embryos via G-protein dependent signaling. This project of the Garcia-Marcos Lab was carried out in collaboration with the Dominguez Lab (Dept. of Medicine) and the Cifuentes Lab (Dept. of Biochemistry) at BU.

G-protein discoveries

By mlayneDecember 19th, 2018in Departmental News, MGM lab, Research News

The Garcia-Marcos lab has recently published two studies in the Journal of Biological Chemistry on the topic of heterotrimeric G protein signaling. Marcin Maziarz, a postdoctoral fellow in the Garcia-Marcos lab, is the first author in both of them. The first study, which was selected as an Editors’ Pick, describes a novel pipeline for the discovery and validation of G protein activators that are not GPCRs, which are the “classic” G protein activators. By screening candidate cytoplasmic proteins containing a putative Gα-binding-and-activating (GBA) motif and using various in vitro and cell-based assays, the lab identified PLCδ4b as a new non-receptor G protein activator.

In the second study, the lab interrogated the mechanism of action of mutant G proteins known to drive uveal melanoma, a cancer of the eye which lacks effective therapies. Interestingly, they found that one frequent mutation, Q209P in the G protein Gαq, leads to G protein activation through a unique and unanticipated mechanism that could be leveraged to develop novel therapeutics for this cancer type.