Phosphatidylinositol 5-phosphate 4-kinase (PIP4K) regulates TOR signaling and cell growth during Drosophila development

Abstract

During development, Drosophila larvae undergo a dramatic increase in body mass wherein nutritional and developmental cues are transduced into growth through the activity of complex signaling pathways. Class I phosphoinositide 3-kinases have an established role in this process. In this study we identify Drosophila phosphatidylinositol 5-phosphate 4-kinase (dPIP4K) as a phosphoinositide kinase that regulates growth during larval development. Loss-of-function mutants in dPIP4K show reduced body weight and prolonged larval development, whereas overexpression of dPIP4K results both in an increase in body weight and shortening of larval development. The growth defect associated with dPIP4K loss of function is accompanied by a reduction in the average cell size of larval endoreplicative tissues. Our findings reveal that these phenotypes are underpinned by changes in the signaling input into the target of rapamycin (TOR) signaling complex and changes in the activity of its direct downstream target p70 S6 kinase. Together, these results define dPIP4K activity as a regulator of cell growth and TOR signaling during larval development.

Deletion of the gene Pip4k2c , a novel phosphatidylinositol kinase, results in hyperactivation of the immune system

“…These data indicate that Pip4k2a and PIP4k2b suppress PI3K-Akt activation but facilitate mTORC1 activation. This model is consistent with the observation that deletion of the single form of PIP4K2 in flies causes suppression of TORC1 activation and suppression of growth (7). To determine the epistasis among the multiple mammalian enzymes, phenotypes of the viable double knockout mice will need to be better examined.…”

“…Mackey et al argued that PI5P4Kγ was negatively regulated by mTORC1 through direct phosphorylation at serine 324 and serine 328 (6). On the other hand, it was reported that knocking out the only PI5P4K isoform in Drosophila resulted in lower body weight and that this correlated with decreased mTORC1 signaling (7). Of particular interest, multiple studies have shown a link between a SNP (rs1678542) in the human PIP4K2C locus and familial autoimmunity (8,9).…”

In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P2to impact mTORC2 and Akt signaling

“…For example, stable knockout of Drosophila dPIP4K (orthologous to the highactivity PIP4K2A in higher species) results in a dramatic attenuation of Akt phosphorylation (20), whereas acute depletion of PIP4K2A in human leukocytes by RNAi results in increased Akt phosphorylation (19). No Akt phenotype was found in PIP4K2A knockout mice (21), but as far as we are aware, cells of the hematopoietic lineage were not studied there; another study from the same group elegantly showed the tissue variability of gene knockouts, with PIP4K2B knockout mice having enhanced insulininduced Akt phosphorylation in skeletal muscle and liver but not in white fat (22).…”

The Hidden Conundrum of Phosphoinositide Signaling in Cancer

“…Unlike PIPKI, the contribution of PIPKII enzyme in PI3K/Akt/mTORC1 appears less dominant and counteracting [40] as the majority of PI(4,5)P 2 is synthesized by PIPKI. However, studies in Drosophila still lend support to the role of PIPKII in cell growth and Akt/mTORC1 signaling ([41]. Additionally, phosphatidic acid which activates different isoforms of PIPKI inhibits endogenous inhibitor of mTORC1, suggesting that PIPKI provide another level of mechanism in regulating the PI3K/Akt/mTORC1 signaling in cancer [42, 43].…”