PIP4K and the role of nuclear phosphoinositides in tumour suppression

Differential profile of PIP4K2A expression in hematological malignancies

“…There has been growing attention to proteins involved in the PtdIns regulation, generating new therapeutic opportunities in solid and hematological cancers [1,2]. Previous studies describe that PIP4K2A or PIP4K2A/B inhibition is able to increase PI3K/AKT and p38 MAPK activation in AML and breast cancer cells [8,11].…”

“…PI3K enzymes are able to generate PtdIns(3,4,5)P 3 from PtdIns(4,5)P 2 , which could be reversed by PTEN activity [1]. In normal hematopoiesis, PI3K activation is important to mediate signal transduction from hematopoietic cell receptors [3].…”

“…PIP4K2A belongs to class II of PIP kinases, which also includes PIP4K2B and PIP4K2C. The main function of this protein family is to recognize and phosphorylate the PtdIns5P in its four position of inositol ring, generating the PtdIns4,5P 2 [1]. Recently, Emerling and colleagues [11] reported that inhibition of both PIP4K2A and PIP4K2B reduced cell survival in vitro of p53-mutated breast cancer cells, and that p53 −/− PIP4K2A −/− PIP4K2B +/− mice presented lower tumor burden and increased tumor free survival compared with p53 −/− PIP4K2A +/+ PIP4K2B +/+ mice [11], which brought attention to the importance of this protein family to cancer development.…”

“…PtdIns may be reversibly phosphorylated at the 3, 4 and/or 5 positions of its inositol ring to generate seven different phosphoinositide species, which are regulated by a set of kinases and phosphatases proteins that are responsible for the generation and maintenance of different pools of each species of PtdIns [1,2].…”

A short history of inositol lipids

“…So this batch of 32 PI(4,5)P 2 was instead labeled in the 4-position, and consequently the predominant 5-phosphatse activity of the enzyme being studied now generated copious quantities of radiolabeled PIP! The identification in animal tissues of the natural substrate of type II PIP kinases (now known as PI5P4Ks), PI5P, followed (84), and this lipid is now also established as having multiple effectors in the cytoplasm and nucleus [see (85)(86)(87) for reviews].…”