Inositol polyphosphate multikinase is a metformin target that regulates cell migration

Metformin has been shown to alter cell adhesion protein expression, which is thought to play a role in its observed antitumor properties. We found that metformin treatment down-regulated integrin beta 1 concomitant with the loss of inositol polyphosphate multikinase (IPMK) in murine myocytes, adipocytes, and hepatocytes. To determine if IPMK was upstream of integrin beta 1 expression, we examined IPMK-/- mouse embryonic fibroblast cells and found that integrins beta 1 and beta 3 gene expression was reduced by half, relative to wild-type cells, whereas focal adhesion kinase (FAK) activity and Rho/Rac/Cdc42 protein levels were increased, resulting in migration defects. Using nanonet force microscopy, we determined that cell:extracellular matrix adhesion and cell contractility forces were decreased, confirming the functional relevance of integrin and Rho protein dysregulation. Pharmacological studies showed that inhibition of both FAK1 and proline-rich tyrosine kinase 2 partially restored integrin beta 1 expression, suggesting negative regulation of integrin beta 1 by FAK. Together our data indicate that IPMK participates in the regulation of cell migration and provides a potential link between metformin and wound healing impairment.