Rôle de la phosphorylation sur tyrosine dans la régulation de l'activité de PPARγ

Authors: Lavallée-Bourget, Marie-Hélène
Advisor: Marette, André
Abstract: Obesity and its complications such as type 2 diabetes and non-alcoholic fatty liver disease are becoming worldwide health concerns and more insights into the underlying physiopathological mechanisms are necessary to improve the treatment of these conditions. Peroxisome proliferator activated receptor gamma (PPARγ) protein is well known for its anti-inflammatory, insulin sensitizing and pro-adipogenic roles. Previous results showed that in absence of the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (Shp1), PPARγ activity is increased. PPARγ activation by thiazolidinediones (TZD) is used in the control of diabetes but is also linked to unwanted side effects. We investigated a new mechanism of regulation of PPARγ activity. We show that Shp1 and PPARγ interact and that PPARγ is tyrosine phosphorylated. Our results suggest that Shp1-mediated dephosphorylation of PPARγ reduces its activity. Molecular modeling analyses further suggest that the interaction between Shp1 and PPARγ depends upon the phosphorylation of one specific residue, tyrosine 355. This residue is also important for the binding with rosiglitazone, a member of the TZD drug class. Mutagenesis experiments showed that the absence of phosphorylation on tyrosine residue 355 decreases PPARγ activity, while its phosphorylation tends to increase it. Despite the fact that many post-translational modifications have been reported in the literature, tyrosine phosphorylation of PPARγ remains mostly unexplored. These results suggest a new PPARγ regulating mechanism that could be exploited to elaborate new PPARγ ligands to improve the treatment of type 2 diabetes and to limit side effects.
Document Type: Mémoire de maîtrise
Issue Date: 2016
Open Access Date: 25 January 2019
Permalink: http://hdl.handle.net/20.500.11794/33285
Grantor: Université Laval
Collection:Thèses et mémoires

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