title: PIKfyve and its Lipid products in health and in sickness.
abstract: PIKfyve, a phosphoinositide 5-kinase synthesizing PtdIns(3,5)P₂ and PtdIns5P in a cellular context, belongs to an evolutionarily ancient gene family of PtdIns(3,5)P₂-synthesizing enzymes that, except for plants, are products of a single-copy gene across species. In the dozen years after its discovery, enormous progress has been made in characterizing the numerous PIKfyve cellular functions and the regulatory mechanisms that govern these functions. It became clear that PIKfyve does not act alone but, rather, it engages the scaffolding regulator ArPIKfyve and the phosphatase Sac3 to make a multiprotein "PAS" complex, so called for the first letters of the protein names. This complex relays antagonistic signals, one for synthesis, another for turnover of PtdIns(3,5)P₂, whose dysregulated coordination is linked to several human diseases. The physiological significance for each protein in the PAS complex is underscored by the early lethality of the mouse models with disruption in any of the three genes. This chapter summarizes our current knowledge of the diverse and complex functionality of PIKfyve and PtdIns(3,5)P₂/PtdIns5P products with particular highlights on recent discoveries of inherited or somatic mutations in PIKfyve and Sac3 linked to human disorders.
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. ashishev@med.wayne.edu
authors.forename: Assia
authors.initials: A
authors.lastname: Shisheva
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001343:Autophagy; D004705:Endocytosis; D066246:ErbB Receptors / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017434:Protein Structure, Tertiary
chemical_list: D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; C113567:phosphatidylinositol 5-phosphate; C120564:Sac3 protein kinase; C492139:PIKFYVE protein, human