The Blind Lab

IPMK generates several inositol phosphate species that are well known to be required for proper cell growth. IPMK also regulates adenosine monophosphate-activated kinase (AMPK), a master regulator of cellular energy homeostasis in the liver. IPMK interacts with AMPK in response to high glucose in mouse hypothalamic cell lines, preventing AMPK phosphorylation and activation. Further, high glucose induces phosphorylation of IPMK on tyrosine 174, and the glucose-induced interaction between IPMK and AMPK is eliminated if IPMK tyrosine 174 is mutated.

IPMK is further linked to cellular energy metabolism by the widely used anti-diabetic drug metformin. Metformin is able to induce AMPK phosphorylation in mouse fibroblasts, however genetic ablation of IPMK prevents metformin activation of AMPK phosphorylation. Further, only the kinase-active IPMK is able to rescue sensitivity to metformin, suggesting that inositol phosphate metabolism plays a role in metformin action.

Metformin has recently been shown to increase survival in human patients with liver cancer, and metformin decreases human liver cancer cell line growth, invasiveness and migration. This is especially intriguing since IPMK expression is highest in the human liver. Taken together, these data suggest that inositol phosphates generated by IPMK might regulate AMPK activation in response to altered cellular energy status by glucose or metformin.

The overall hypothesis I am testing in the Blind lab is that inositol phosphates generated by IPMK connect AMPK to metformin action in liver cells. We test this hypothesis by determining if IPMK tyrosine 174 phosphorylation regulates IPMK kinase activity in human cells,  determine how inositol phosphates mediate metformin action in human cells, and determine if IPMK mediates the cancer-protective effects of metformin in human cells.

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