Regulation of innate immunity by inositol 1,3,4,5-tetrakisphosphate

Jia, Yonghui; Schurmans, Stéphane; Luo, Hongbo

doi:10.4161/cc.7.18.6688

Cited by 14 publications

(38 citation statements)

References 37 publications

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“…In contrast, a number of reports indicate that higher-order inositol phosphates antagonize proliferation and tumorigenesis and promote apoptosis (24)(25)(26)(27)(28)(29). Moreover, several studies indicate that higher inositol phosphates specifically decrease Akt activity (26,27,(30)(31)(32). The differential regulation of PIP 3 and inositol phosphate production by IPMK may provide a process enabling cells to switch between Akt activation and inhibition, with corresponding influences upon cellular proliferation and survival (Fig.…”

Section: Resultsmentioning

confidence: 89%

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

Maag

Maxwell

Hardesty

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

105

141

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The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation, and survival, in large part by activating the protein kinase Akt/PKB. We show that inositol polyphosphate multikinase (IPMK) physiologically generates PIP 3 as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP 3 generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.signal transduction | cancer A large family of inositol phosphates serves multiple functions, with inositol 1,4,5-trisphosphate (IP 3 ) being well known as a second messenger releasing intracellular calcium (1). Inositol diphosphates, incorporating an energetic pyrophosphate bond, display numerous physiological roles, including pyrophosphorylation of a variety of protein targets (2-4). These inositol pyrophosphates are synthesized by a family of IP 6 kinase enzymes (5). Recently, novel isomers of inositol pyrophosphates have been described that are synthesized by a distinct inositol phosphate kinase enzyme designated Vip1 (6, 7).Inositol polyphosphate multikinase (IPMK) is a member of the IP 6 kinase family of enzymes but is not primarily associated with the formation of inositol pyrophosphates. Instead it generates several inositol phosphates, converting IP 3 to IP 4 and IP 4 to IP 5 , with its primary physiologic role in this pathway being to form the bulk of IP 5 in cells (5,(8)(9)(10)(11). IPMK also possesses phosphatidylinositol 3-kinase (PI3K) activity in vitro (12), specifically phosphorylating phosphatidylinositol(4,5)-bisphosphate (PIP 2 ) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), a second messenger known to promote cellular growth, proliferation, survival, and migration (13). The physiologic role of this activity has not heretofore been established. The principal PI3K activity in cells has been attributed to a family of enzymes identified by Cantley and associates (reviewed in ref. 14), whose catalytic subunits are designated p110. PIP 3 generated by p110 in response to extracellular stimuli, such as growth factors, is a principal stimulus of the Akt/mammalian target of rapamycin (mTOR) signaling pathway, which in turn regulates protein synthesis and plays a role in some cancers (15)(16)(17).We wondered whether the PI3K activity of IPMK contributes to the generation of PIP 3 under physiologic conditions to influence Akt signaling and cell growth. There is good reason to assume that IPMK is ...

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Section: Resultsmentioning

confidence: 89%

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

Maag

Maxwell

Hardesty

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

105

141

View full text Add to dashboard Cite

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“…Reports have indicated that myo-inositol was likely involved in phagocytosis1920. Given that depolarization contributes to phagocytosis21, we reasoned that myo-inositol alters the depolarization of macrophages, and in turn promotes phagocytosis to cope with BLFX-S and BLFX-R. To examine this idea, we first tested whether myo-inositol depolarized macrophages, the depolarization elevated the membrane potential difference between macrophages and bacteria, and thereby increased phagocytosis.…”

Section: Resultsmentioning

confidence: 99%

Myo-inositol improves the host’s ability to eliminate balofloxacin-resistant Escherichia coli

Chen

Zhang

et al. 2015

Sci Rep

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Antibiotic-resistant mechanisms are associated with fitness costs. However, why antibiotic-resistant bacteria usually show increasing adaptation to hosts is largely unknown, especially from the host’s perspective. The present study reveals the host’s varied response to balofloxacin-resistant Escherichia coli (BLFX-R) using an integrated proteome and metabolome approach and identifies myo-inositol and phagocytosis-related proteins as crucial biomarkers. Originally, macrophages have an optimal attractive preference to BLFX-S due to more polarization of BLFX-S than BLFX-R, which renders faster elimination to BLFX-S than BLFX-R. The slower elimination to BLFX-R may be reversed by exogenous myo-inositol. Primarily, myo-inositol depolarizes macrophages, elevating adherence to both BLFX-S and BLFX-R. Since the altered adherence is equal to both strains, the myo-inositol-treated macrophages are free of the barrier to BLFX-R and thereby promote phagocytosis of BLFX-R. This work provides a novel strategy based on metabolic modulation for eliminating antibiotic-resistant bacteria with a high degree of host adaptation.

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“…Some of the roles of ITPKs in innate immunity are depicted in Fig. 4d, e, and this topic was recently reviewed [120].…”

Section: Widespread Roles For Itpks In the Immune Responsementioning

confidence: 99%

“…In contrast to the other immune models, no gainof-function role for Ins(1,3,4,5)P 4 is invoked. d ITPKB also plays widespread roles in the innate immune system [120]. In neutrophils, Ins(1,3,4,5)P 4 generated downstream of Fc receptor (FcR) activation is proposed to compete with the head group of the lipid phosphatidylinositol (3,4,5)P 3 (PIP 3 ) for binding to the tyrosine kinase AKT.…”

Section: Widespread Roles For Itpks In the Immune Responsementioning

confidence: 99%

“…The localized, Ca 2? -dependent generation of Ins(1,3,4,5)P 4 from Ins(1,4,5)P 3 can be imagined to participate in many of these processes, and investigations into ITPKB functions in immune development, tolerance, selection, and memory will remain fruitful areas of research for the foreseeable future [12,120,122].…”

Section: Widespread Roles For Itpks In the Immune Responsementioning

confidence: 99%

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Inositol trisphosphate 3-kinases: focus on immune and neuronal signaling

Schell

2010

Cell. Mol. Life Sci.

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The localized control of second messenger levels sculpts dynamic and persistent changes in cell physiology and structure. Inositol trisphosphate [Ins(1,4,5)P(3)] 3-kinases (ITPKs) phosphorylate the intracellular second messenger Ins(1,4,5)P(3). These enzymes terminate the signal to release Ca(2+) from the endoplasmic reticulum and produce the messenger inositol tetrakisphosphate [Ins(1,3,4,5)P(4)]. Independent of their enzymatic activity, ITPKs regulate the microstructure of the actin cytoskeleton. The immune phenotypes of ITPK knockout mice raise new questions about how ITPKs control inositol phosphate lifetimes within spatial and temporal domains during lymphocyte maturation. The intense concentration of ITPK on actin inside the dendritic spines of pyramidal neurons suggests a role in signal integration and structural plasticity in the dendrite, and mice lacking neuronal ITPK exhibit memory deficits. Thus, the molecular and anatomical features of ITPKs allow them to regulate the spatiotemporal properties of intracellular signals, leading to the formation of persistent molecular memories.

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Regulation of innate immunity by inositol 1,3,4,5-tetrakisphosphate

Cited by 14 publications

References 37 publications

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

Myo-inositol improves the host’s ability to eliminate balofloxacin-resistant Escherichia coli

Inositol trisphosphate 3-kinases: focus on immune and neuronal signaling

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