Contact info

Dr Louise Larose
McGill University
Strathcona Building
3640, University St. - Room W315
Montr�al, QC H3A 2B2

Tel: 1-514-398-5844
Fax: 1-514-398-3923
E-mail: [email protected]

Research keywords

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Since 1995, the main interest of my laboratory is the mechanisms involved in the development of cancer and diabetes. Particularly, we study the role of SH2/SH3 domains-containing adaptor proteins such Nck, in mediating critical cellular functions. We have contributed to the identification and the physiological meaning of a number of Nck interacting proteins and network complexes.

We have significantly contributed to characterize the mammalian Casein Kinase I-γ2 (CKI-γ2) for which very little was known. We demonstrated that CKI-γ2 interacts with Nck (Lussier and Larose. JBC 272:2688-94, 1997) and established that CKI-γ2 by phosphorylating the ligand bound β-PDGF receptor inhibits PDGF-R activity (Bioukar et al., JBC 274:1457-63, 1999). Our recent data show that overexpression of CKI-γ2 in fibroblasts inhibits the formation of actin stress fibres and delays cell cycle progression in G1 (manuscript in preparation).

However, I believe that our most significant contribution is the discovery of a novel unpredicted role for the adaptor protein Nck in regulating translation and signaling from the endoplasmic reticulum (ER). Our work has revealed that signaling mechanisms involving Nck, initially thought to take place exclusively at the plasma membrane, also take place at the ER and significantly impact on crucial biological responses.

We were the first to discover a role for Nck in modulating translation (Kebache et al., PNAS 99:5406-11, 2002). We uncovered that Nck directly acts on the translational machinery through its interaction with the β subunit of the eukaryotic initiation factor 2 (eIF-2β) and we established that Nck is required for optimal protein synthesis (Kebache et al., JBC 279:9662-71, 2004). We demonstrated that Nck antagonizes the translational regulatory component of the ER response to stress produced by accumulation of unfolded protein in this organelle. We collaborated with Dr E. Chevet to demonstrate that Nck at the reticulum endoplasmic level, controls MAPK activation by the ER (Nguyen et al., Mol Cell Biol 15:4248-4260, 2004). We established that Nck modulates eIF2β phosphorylation by a subset of eIF2β-kinases (Cardin et al., FEBS J 274:5865-5875, 2007). In a recent study, we uncovered that mice deleted of Nck-1 are protected against obesity-induced insulin resistance due to impaired ER stress response in liver and muscle (Latreille et al., Diabetes, Second Revision 2008).

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Our present research activities involve:

1. Insulin resistance and pancreatic β-cell function. Previous findings from our laboratory involved the adaptor proteins Nck in signaling initiated in response to stress imposed to the endoplasmic reticulum (ER). Using Nck knock out mice, we recently established that Nck plays an important role in ER stress mediated insulin resistance induced by obesity. In the same study, we also noticed pancreatic β-cells defect in Nck knock out mice. Our main goals are to delineate the fine mechanisms by which Nck regulates insulin sensitivity of peripheral tissues, but also pancreatic β-cell homeostasis.

2. Cancer progression. Our most recent data strongly argue that increased expression of Nck-2 in primary cancer cell lines that are poorly metastatic may be determinant for these cells to adopt an aggressive metastatic phenotype. Our goal is to identify the mechanisms by which higher levels of Nck-2 promote migration in cancer cells and metastasis in live animals.

3. Phosphorylation network. We wish to determine the impact of phosphorylation on Nck adaptor function and localization. This includes to identify protein kinases which phosphorylate Nck, to determine in which cell conditions Nck become phosphorylated, to map the phosphorylation sites on Nck, to generate phosphospecific antibodies against these sites and to analyze in cells the behavior of Nck mutants that are no longer phosphorylated on specific sites.