IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice

Siegemund, Sabine; Rigaud, Stéphanie; Conche, Claire; Broaten, Blake; Schaffer, Lana; Westernberg, Luise; Head, Steven R.; Sauer, Karsten

doi:10.1182/blood-2014-06-583187

Cited by 28 publications

(71 citation statements)

References 77 publications

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“…Itpkb deletion in mice thus causes increased mTORC1 activity and phenotypic HSC expansion, similar to Wip1 deletion (Chen et al, 2015;Siegemund et al, 2015). Similar to other HSC studies (Chen et al, 2015), rapamycin blocks phenotypic HSC expansion in Itpkb-knockout mice, reinforcing the notion that mTORC1 drives HSC proliferation (Siegemund et al, 2015).…”

Section: Hematopoietic Stem Cellssupporting

confidence: 73%

“…Phenotypic HSC expansion in Wip1-KO mice is blocked by rapamycin, indicating that HSC proliferation is driven by mTORC1 (Chen et al, 2015). In addition, inositol-trisphosphate 3-kinase B (ITPKB), a lipid kinase that produces inositol (1,3,4,5)-tetrakisphosphate [IP 4 ; Ins(1,3,4,5)P 4 ], is essential for HSC maintenance and acts by limiting AKT-mTORC1 activation (Siegemund et al, 2015); IP 4 produced by ITPKB limits the recruitment of AKT to the cell membrane by serving as a PIP 3 decoy (Siegemund et al, 2015), resulting in decreased AKT and mTORC1 activation. Itpkb deletion in mice thus causes increased mTORC1 activity and phenotypic HSC expansion, similar to Wip1 deletion (Chen et al, 2015;Siegemund et al, 2015).…”

Section: Hematopoietic Stem Cellsmentioning

confidence: 99%

“…In addition, inositol-trisphosphate 3-kinase B (ITPKB), a lipid kinase that produces inositol (1,3,4,5)-tetrakisphosphate [IP 4 ; Ins(1,3,4,5)P 4 ], is essential for HSC maintenance and acts by limiting AKT-mTORC1 activation (Siegemund et al, 2015); IP 4 produced by ITPKB limits the recruitment of AKT to the cell membrane by serving as a PIP 3 decoy (Siegemund et al, 2015), resulting in decreased AKT and mTORC1 activation. Itpkb deletion in mice thus causes increased mTORC1 activity and phenotypic HSC expansion, similar to Wip1 deletion (Chen et al, 2015;Siegemund et al, 2015). Similar to other HSC studies (Chen et al, 2015), rapamycin blocks phenotypic HSC expansion in Itpkb-knockout mice, reinforcing the notion that mTORC1 drives HSC proliferation (Siegemund et al, 2015).…”

Section: Hematopoietic Stem Cellsmentioning

confidence: 99%

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mTOR signaling in stem and progenitor cells

2018

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The mammalian target of rapamycin (mTOR) senses nutrients and growth factors to coordinate cell growth, metabolism and autophagy. Extensive research has mapped the signaling pathways regulated by mTOR that are involved in human diseases, such as cancer, and in diabetes and ageing. Recently, however, new studies have demonstrated important roles for mTOR in promoting the differentiation of adult stem cells, driving the growth and proliferation of stem and progenitor cells, and dictating the differentiation program of multipotent stem cell populations. Here, we review these advances, providing an overview of mTOR signaling and its role in murine and human stem and progenitor cells.

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Section: Hematopoietic Stem Cellssupporting

confidence: 73%

Section: Hematopoietic Stem Cellsmentioning

confidence: 99%

Section: Hematopoietic Stem Cellsmentioning

confidence: 99%

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mTOR signaling in stem and progenitor cells

2018

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“…ITPKA knock-out mice exhibit increased synaptic plasticity and slight impairments of learning and memory [17,18], while deletion of ITPKB resulted in impaired stem cell homeostasis of immune cells [19]. ITPKC knock-out mice do not show an obvious altered phenotype [20] but a clinical relevant mutation of ITPKC is described in Kawasaki disease [21].…”

Section: Discovery and Catalytic Role Of Itpksmentioning

confidence: 99%

Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types

Windhorst

Song

Gazdar

2017

Biochemical Pharmacology

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At present targeted tumor therapy is based on inhibition of proteins or protein mutants that are up-regulated in tumor but not in corresponding normal cells. The actin bundling Inositol-trisphosphate 3-kinase A (ITPKA) belongs to such molecular targets. ITPKA is expressed in a broad range of tumor types but shows limited expression in normal cells. In lung and breast cancer expression of ITPKA is stimulated by gene body methylation which increases with increasing malignancy of these tumors but is not detectable in the corresponding normal tissues. Since ITPKA gene body methylation occurs early in tumor development, it could serve as biomarker for early detection of lung cancer. Detailed mechanistic studies revealed that down-regulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis. It is assumed that tumor growth is stimulated by the InsP3Kinase activity of ITPKA and metastasis by its actin bundling activity. A selective inhibitor against the InsP3Kinase activity of ITPKA has been identified but compounds inhibiting the actin bundling activity are not available yet. Since no curative therapy option for metastatic lung or breast tumors exist, therapies that block activities of ITPKA may offer new options for patients with these tumors. Thus, efforts should be made to develop clinical drugs that selectively target InsP3Kinase activity as well as actin bundling activity of ITPKA.

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“…Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance to mediate the survival signaling of B cells and T cell receptor signaling (26)(27)(28)(29). In addition, ITPKB controls hematopoietic stem cell homeostasis through AKT and mTOR signaling (30). However, few studies link ITPKB to human solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance

Pan¹,

Jin²,

Wang³

et al. 2019

Journal of Clinical Investigation

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IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice

Abstract: • Itpkb produces the soluble messenger IP 4 , which limits cytokine-induced Akt/ mTORC1 activation in HSC.• Itpkb loss in mice activates HSC and impairs their longevity and function, resulting in lethal hematopoietic failure and anemia.

Cited by 28 publications

References 77 publications

mTOR signaling in stem and progenitor cells

mTOR signaling in stem and progenitor cells

Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types

Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance

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