PAK1 and PAK2 in the cell metabolism regulation

P21-activated kinases (PAK) regulate processes associated with cytoskeletal rearrangements, such as cell division, adhesion, and migration. Possible regulatory role of PAK in the cell metabolism is little explored, but increasing evidence suggests that a cell metabolic phenotype is related to cell interaction with the microenvironment. We analyzed the impact of PAK inhibition by small molecule inhibitors, small interfering RNA, or by gene knock-out on the rates of mitochondrial respiration and aerobic glycolysis. Pharmacological inhibition of PAK group I by IPA-3 induced a strong decrease of the both metabolic rates in adherent cancer cell lines, leukemia/lymphoma cell lines, and primary leukemia cells. The effect of FRAX597, which inhibits PAK kinase activity only, was moderate, indicating that PAK non-kinase functions are essential for the cell metabolism. Selective downregulation or deletion of PAK2 was associated with a shift towards oxidative phosphorylation. However, the overall metabolic capacity was not substantially reduced by PAK1 or PAK2 deletion, possibly due to partial redundancy in PAK1/PAK2 regulatory roles.