Research interests

Our main interest is to understand how mitogens and oncogenes regulate cell growth and proliferation. We focus our research on signal transduction pathways often deregulated in metabolic diseases and cancer.

Characterize novel effectors of the Ras/ERK signalling pathway. Ras/ERK signalling is activated by many growth factors and controls essential biological processes, including cell cycle progression, cell differentiation, survival and motility. Proper regulation of this pathway is crucial as activating/inactivating mutations within this cascade lead to various genetic disorders and diseases, including cancer. Activating mutations in Ras are found in up to 30% of all human cancers and are particularly common in pancreatic (90%) and colon cancers (50%). B-RAF mutations have a more narrow distribution, but are prevalent in melanoma (63%), papillary thyroid cancers (45%), and low-grade ovarian cancers (36%). Using phosphoproteomic and tandem-affinity purification approaches, we have identified a number of Ras-regulated phosphosubstrates and are currently characterizing their roles as novel Ras effectors.

Determine the biological function of the p90 ribosomal S6 kinase (RSK) family of protein kinases. The RSK family of protein kinases contains four human isoforms, RSK1, RSK2, RSK3 and RSK4, that also belong to the AGC superfamily of Ser/Thr kinases. RSK-related molecules have also been identified in Caenorhabditis elegans (T01H8.1) and Drosophila melanogaster (RPS6-protein kinase-II). The RSK isoforms are directly activated by ERK1 and ERK2 in response to Ras pathway activation, but very little is know about the roles they play in Ras-dependent biological functions. Our group is using mouse genetics and several gain- and loss-of-function strategies to delineate the isoform-specific function of the RSK family. We have also identified novel RSK substrates that help understand the wide range of biological functions the RSK isoforms appear to be controlling.

Characterize the regulation and function of the mammalian target of rapamycin (mTOR) pathway. The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that regulates cell growth as well as organ and body size in a variety of organisms. mTOR was discovered as the molecular target of rapamycin, an antifungal agent used clinically as an immunosuppressant and more recently, as an anti-cancer drug. Emerging evidence indicates that deregulation of the mTOR pathway occurs in many types of cancer, underscoring the importance of understanding how this pathway is regulated by oncogenic and mitogenic cues. mTOR forms two distinct multiprotein complexes, the rapamycin-sensitive and -insensitive mTOR complex (mTORC) 1 and 2, respectively. Activated mTORC1 phosphorylates two main regulators of mRNA translation and ribosome biogenesis, S6K1 and 4E-BP1, thus stimulating protein synthesis. The key upstream player regulating mTORC1 activity is the small GTPase Rheb, which is negatively regulated by the TSC1-TSC2 GTPase-activating protein (GAP) complex. Several pathways modulate TSC1-TSC2 activity toward Rheb, and thereby promote mTORC1 activity. We have found that Ras/ERK signalling positively regulates mTORC1 activity through ERK- and RSK-mediated phosphorylation of TSC2 and Raptor. Our group is pursuing these observations by determining the role played by the Ras/ERK pathway in mTOR signalling.

Interplay between mechanical and biological mechanisms during cell cortex assembly. The cell cortex is a network of actin, myosin and associated proteins that underlies the plasma membrane and determines the shape of the cell body. The cortex enables the cell to resist externally applied stresses and exert mechanical work. As such, it plays a role in normal physiology during events involving cell deformation such as mitosis, cytokinesis, and cell locomotion, and in the pathophysiology of diseases such as cancer where cortical contractility is upregulated. Despite its importance, little is known about how the cortex assembles, how it is tethered to the cell membrane, and how its mechanical properties are regulated. The aim of this project is to uncover the molecules involved in cortex assembly, understand their regulation, determine how cortex mechanical properties relate to cortical ultrastructure and proteic composition, and explore how cortical mechanics in turn influence molecular concentrations and activities. We propose to use blebs, cell protrusions transiently devoid of cortex, and metaphase cells, which have a well-defined cortex, as model systems to study the actin cortex. This interdisciplinary project, in collaboration with Guillaume Charras (UCL), Ewa Paluch (MPI-Dresden), and Guillaume Romet-Lemonne (CNRS), will enable us to rationally link proteic composition, ultrastructure, mechanics and regulation of the cortex to one another. 

Actin cytoskeleton of a blebbing cell (image provided by Guillaume Charras)