Subventions et des contributions :

Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023)

Organs and tissues perceive cues from the external milieu through the use of receptors at their cell surface. These cues have major impacts on the cells’ behavior such as influencing their decision to divide, differentiate, move, secrete hormones, etc. Upon signal reception, receptors transmit information through signal transduction pathways that target signals to precise intracellular destinations. Signals are then interpreted by cellular machineries that implement specific responses.

My lab has been working for several years on a key signaling pathway known as the Ras-MAPK pathway that transmits upstream signals dictating cells to proliferate or to differentiate. At its core, the pathway involves four enzymes, namely, Ras (a GTPase), and three kinases known as RAF, MEK, and MAPK. Upon activation by cell surface receptors, Ras activates RAF, which in turn leads to the activation of MEK and MAPK. Active MAPK then modifies the activity of hundreds of proteins, and thereby triggers adapted cell responses.

The enzymatic process by which RAF, MEK, and MAPK transfer the signals is known as phosphorylation. This event adds a phosphate group to target proteins, which in turn modulates their activity. The components and signaling mechanism of the Ras-MAPK pathway have been conserved during evolution. For this reason, my lab exploits Drosophila fruit flies as a model to identify new components of the Ras-MAPK pathway. We recently conducted a genetic screen that surveyed each gene in flies for its potential role in Ras-MAPK signaling. In addition to new factors that control the phosphorylation cascade, we identified several new proteins that impacted the levels of the MAPK protein. This unexpected finding suggests that MAPK levels are regulated by a set of factors that in turn impinge on Ras-MAPK signaling.

Currently, little is known on the mechanisms that regulate the levels of core signal transduction factors such as MAPK. We propose here a research program to investigate the underlying principles. On the one hand we will characterize the mechanisms by which specific factors impinge on Drosophila MAPK levels. On the other hand, we will identify the physiological signals that regulate these factors and their biological consequences with respect to Ras-MAPK signaling during Drosophila development.

This research program is at the forefront of the signaling field. It will bring a new understanding to the regulation of signal transduction mechanisms as well as provide mechanistic insights on new biochemical processes. In addition, this work may lead to the development of cell-based tunable devices to control cell proliferation and differentiation events leading to tissue engineering.