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Phosphoinositides and Disease pp 127–162Cite as

PIKfyve and its Lipid Products in Health and in Sickness

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 362))

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.

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Acknowledgments

I am grateful to the past and current members of my laboratory, and particularly to Drs. Ogi Ikonomov and Diego Sbrissa for their excellent work and stimulating discussions. I thank Dr. Steven Cala for his insightful comments and Violeta Shisheva for her many years of support. The work described from my laboratory was funded by ADA, JDFI, and NIH.

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  1. Department of Physiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, Michigan, 48201, USA

    Assia Shisheva

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  1. CTR DIABETES BARTS, Queen Mary University of London, UK, NEWARK ST 4, LONDON E1 2AT, United Kingdom

    MARCO FALASCA

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Shisheva, A. (2012). PIKfyve and its Lipid Products in Health and in Sickness. In: FALASCA, M. (eds) Phosphoinositides and Disease. Current Topics in Microbiology and Immunology, vol 362. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5025-8_7

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