Faculty Opinions recommendation of Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity.

AbstractInositol polyphosphate multikinase (IPMK) is a rate-limiting enzyme in the inositol phosphate (IP) pathway which converts IP3 to IP4 and IP5. In mammalian cells, IPMK can also act as a phosphoinositol-3-kinase (PI3-kinase). We previously found that IPMK is a critical PI3-kinase activator of AKT. Here, we show that IPMK mediates AKT activation by promoting membrane localization and activation of PDK1. The PI3-kinase activity of IPMK is dispensable for membrane localization of AKT, which is entirely controlled by classical PI3-kinase (p110α,ß, γ, δ). By contrast, we found that PDK1 membrane localization was largely independent of classical PI3-kinase. Membrane localization of PDK1 stimulates cell migration by dissociating ROCK1 from inhibitory binding to RhoE and promoting ROCK1-mediated myosin light chain (MLC) phosphorylation. Deletion of IPMK impairs cell migration associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent MLC phosphorylation. To investigate the physiological relevance of IPMK-mediated AKT activation, we generated mice selectively lacking IPMK in epithelial cells of the intestine, where IPMK is highly expressed. Deletion of IPMK in intestinal epithelial cells markedly reduced AKT phosphorylation and diminished numbers of Paneth cells – a crypt-resident epithelial cell type that generates the physiological niche for intestinal stem cells. Ablation of IPMK impaired intestinal epithelial cell regeneration basally and after; chemotherapy-induced damage, suggesting a broad role for IPMK in the activation of AKT and intestinal tissue regeneration. In summary, the PI3-kinase activity of IPMK promotes membrane localization of PDK1, a critical kinase whereby AKT maintains intestinal homeostasis.One Sentence SummaryPI3-kinase activity of IPMK is essential for activation of AKT.

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Faculty Opinions recommendation of Amino acid signaling to mTOR mediated by inositol polyphosphate multikinase.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8693959.11171056 ◽

2011 ◽

Author(s):

Joseph Avruch ◽

Angela Papageorgiou

Keyword(s):

Amino Acid ◽

Inositol Polyphosphate ◽

Inositol Polyphosphate Multikinase ◽

Amino Acid Signaling

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Role of the Inositol Polyphosphate Multikinase Ipk2 in Regulation of Hyphal Development, Calcium Signaling and Secretion in Candida albicans

Mycopathologia ◽

10.1007/s11046-017-0138-4 ◽

2017 ◽

Vol 182 (7-8) ◽

pp. 609-623 ◽

Cited By ~ 6

Author(s):

Jianrong Li ◽

Bing Zhang ◽

Tianyu Ma ◽

Honggang Wang ◽

Biao Zhang ◽

...

Keyword(s):

Candida Albicans ◽

Calcium Signaling ◽

Inositol Polyphosphate ◽

Hyphal Development ◽

Inositol Polyphosphate Multikinase

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Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1511810112 ◽

2015 ◽

Vol 112 (31) ◽

pp. 9751-9756 ◽

Cited By ~ 16

Author(s):

Ishrat Ahmed ◽

Juan I. Sbodio ◽

Maged M. Harraz ◽

Richa Tyagi ◽

Jonathan C. Grima ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Kinase Activity ◽

Inositol Phosphate ◽

Cell Model ◽

Inositol Polyphosphate ◽

Interacting Protein ◽

Lipid Kinase ◽

Inositol Polyphosphate Multikinase ◽

Neural Dysfunction

Huntington’s disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.

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Inositol Polyphosphate Multikinase Is a Coactivator of p53-Mediated Transcription and Cell Death

Science Signaling ◽

10.1126/scisignal.2003405 ◽

2013 ◽

Vol 6 (269) ◽

pp. ra22-ra22 ◽

Cited By ~ 30

Author(s):

R. Xu ◽

N. Sen ◽

B. D. Paul ◽

A. M. Snowman ◽

F. Rao ◽

...

Keyword(s):

Cell Death ◽

Inositol Polyphosphate ◽

Inositol Polyphosphate Multikinase

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Inositol Polyphosphate Multikinase (IPMK), a Gene Coding for a Potential Moonlighting Protein, Contributes to Human Female Longevity

Genes ◽

10.3390/genes10020125 ◽

2019 ◽

Vol 10 (2) ◽

pp. 125 ◽

Cited By ~ 1

Author(s):

Francesco De Rango ◽

Paolina Crocco ◽

Francesca Iannone ◽

Adolfo Saiardi ◽

Giuseppe Passarino ◽

...

Keyword(s):

Genetic Factors ◽

Inositol Phosphates ◽

Nutrient Sensing ◽

Human Longevity ◽

Cell Physiology ◽

Inositol Polyphosphate ◽

Moonlighting Protein ◽

Key Enzyme ◽

Female Longevity ◽

Inositol Polyphosphate Multikinase

Biogerontological research highlighted a complex and dynamic connection between aging, health and longevity, partially determined by genetic factors. Multifunctional proteins with moonlighting features, by integrating different cellular activities in the space and time, may explain part of this complexity. Inositol Polyphosphate Multikinase (IPMK) is a potential moonlighting protein performing multiple unrelated functions. Initially identified as a key enzyme for inositol phosphates synthesis, small messengers regulating many aspects of cell physiology, IPMK is now implicated in a number of metabolic pathways affecting the aging process. IPMK regulates basic transcription, telomere homeostasis, nutrient-sensing, metabolism and oxidative stress. Here, we tested the hypothesis that the genetic variability of IPMK may affect human longevity. Single-SNP (single nuclear polymorphism), haplotype-based association tests as well as survival analysis pointed to the relevance of six out of fourteen genotyped SNPs for female longevity. In particular, haplotype analysis refined the association highlighting two SNPs, rs2790234 and rs6481383, as major contributing variants for longevity in women. Our work, the first to investigate the association between variants of IPMK and longevity, supports IPMK as a novel gender-specific genetic determinant of human longevity, playing a role in the complex network of genetic factors involved in human survival.

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