The power of five - inositol polyphosphate 5-phosphatase gene mutations at the intersection of development and
Meagan J McGrath1, Elizabeth M Davies2, Lisa M Ooms2
1Department of Biochemistry and Molecular Biology, Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia.
Abstract:
Phosphoinositides are transient signaling lipids, derived from the reversible phosphorylation of phosphatidylinositol on intracellular membranes, which serve as master regulators of many essential cellular functions. Seven distinct phosphoinositide species require precise spatiotemporal control, which is regulated by specific phosphatidylinositol kinases and phosphatases. Here, we review one such family, the inositol polyphosphate 5-phosphatases, which comprise 10 mammalian enzymes that dephosphorylate the 5-position phosphate group from the inositol head group of PtdIns(4,5)P2, PtdIns(3,5)P2, and/or PtdIns(3,4,5)P3. Despite overlapping substrate specificities, the 5-phosphatases play nonredundant roles, including in development, as demonstrated by murine and zebrafish knockout studies. Mutations in several 5-phosphatase family members are associated with multisystem developmental and congenital syndromes. Associations between 5-phosphatase gene variants and diabetes and metabolic syndrome, neurodegenerative disease, and in rare cases cancer, are also emerging. Here, we provide a comprehensive discussion of the latest advances in this field, including updates on disease modeling and mechanisms.
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