Investigating the role of PIP4K in Immune System Regulation and P53-Inactivated Cancers

Abstract

Phosphatidylinositol 5-phosphate 4-kinase (PIP4K) catalyses the formation of phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) which is a messenger involved in important cellular signalling pathways including the PI3K/Akt/mTOR pathway and the phospholipase C pathway. Three isoforms of PIP4K have been identified, namely PIP4K2α, PIP4K2β, and PIP4K2, which have been shown to play roles in cellular activities such as growth, stress response, immune system regulation, and tumour formation. However, the exact mechanisms engaged by the kinases are still obscure. This study focused on investigating the role of PIP4K in modulating the immune system through regulatory T cells (Tregs), and in growth of cancer cells with inactivated p53. Findings from this study showed that PIP4K2β and 2 isoforms regulate PI3K/Akt/mTOR signalling in Tregs to control cell proliferation, survival, and immunosuppressive activity. This study also suggested that PIP4K controls FOXP3 expression, the master transcriptional regulator of Tregs through a novel PI3K/UHRF1/FOXP3 pathway. Previously PIP4K had been shown to play roles in cancer cell growth, and a discovery of possible synthetic lethal interaction with p53 in cancer cells has made this kinase a promising target for cancer therapy. Findings from this study indicate that the synthetic lethality of PIP4K and p53 is not present in all types of cancer. Rather, it is suggested to depend on the specific mutation of p53 and alteration in expression of PIP4K in the cells. Inhibition of PIP4K also regulates the PI3K/Akt pathway differently in different cancer cells. Together, findings from this study suggested that PIP4K modulates both the immune system and cancer cell growth, and its different role in regulating PI3K/Akt/mTOR pathway could be the key to understand how PIP4K modulates the systemic immune response, and how different cancers can benefit from the expression of this family of lipid kinases.

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