Novel roles for the MAPK-interacting serine threonine kinases (Mnks)

Abstract

The mitogen activated protein kinase (MAPK)-interacting serine threonine kinases (Mnks) are components of the MEK/ERK and p38MAPK signalling pathways. Research has focused on the role of the Mnks in tumorigenesis, inflammatory signalling cascades and translation of inflammatory cytokines. The physiological roles of these kinases are still not well understood and their functions have yet to be fully elucidated. This prompted the work presented in this study where the roles of the Mnks have been investigated in the phenomenon of rapamycin-induced eIF4E phosphorylation and the role of the Mnks in glucose and lipid metabolism. Increased eIF4E phosphorylation has been correlated with tumorigenesis and a potential anti-cancer therapy, rapamycin, increases eIF4E phosphorylation in cancer cells. The increase in eIF4E phosphorylation is caused by mTORC1 inhibition-dependent increases in Mnk2a activity. The Mnks are enriched in tissues important for glucose metabolism and here a role for the Mnks has been established in insulin signalling. Investigation revealed that the Mnks phosphorylate IRS1 at 5 sites resulting in its stabilization by impairing its proteasome-mediated degradation. The consequence of Mnk1/2 double knockout in mice is glucose intolerance due to reduced IRS1 protein in white adipose tissue. The incidence of type 2 diabetes as a result of obesity is rising rapidly but the mechanisms responsible are as yet not fully understood. Evidence presented in a patent suggests the Mnks may play a role in lipid metabolism and insulin sensitivity. This inspired research presented here showing Mnk2-KO mice exhibit a lack of weight gain when fed high fat diets. Interestingly the Mnk2-KO mice were resistant to severe diet-induced insulin resistance. This appears to be related to a reduction in chronic inflammation usually associated with high fat diet feeding.

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