PAK1 and PAK2 in cell metabolism regulation

Abstract

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.

Potential COVID‐19 therapeutic approaches targeting angiotensin‐converting enzyme 2; An updated review

“…90 P21-activated kinases, PAK1 and PAK2 are responsible for regulating cell adhesion, migration, and invasion. 91,92 PAK1 is the major 'pathogenic' kinase, whose abnormal activation can lead to cancers, inflammation, malaria, and pandemic viral infection, including influenza, HIV, and COVID-19. 93 Natural and synthetic PAK1-blockers such as propolis, melatonin, ciclesonide, ivermectin, and ketorolac have been suggested as potential therapeutics against COVID-19.…”

“…Cdc42 activates by conformational changes 90 . P21‐activated kinases, PAK1 and PAK2 are responsible for regulating cell adhesion, migration, and invasion 91,92 . PAK1 is the major ‘pathogenic’ kinase, whose abnormal activation can lead to cancers, inflammation, malaria, and pandemic viral infection, including influenza, HIV, and COVID‐19 93 .…”