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

Schell, Michael J.

doi:10.1007/s00018-009-0238-5

Cited by 33 publications

(47 citation statements)

References 212 publications

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“…The differences between SHIP-1 42,43,77 Clearly, more detailed mechanistic studies are needed to discern the respective contributions of Akt/mTORC1-dampening by IP 4 and other mechanisms to HSC control by Itpkb.…”

Section: Discussionmentioning

confidence: 99%

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

Siegemund¹,

Rigaud²,

Conche³

et al. 2015

Blood

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Section: Discussionmentioning

confidence: 99%

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

Siegemund¹,

Rigaud²,

Conche³

et al. 2015

Blood

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“…2,3 In addition to this catalytic activity, it has been shown that ITPKA has Factin bundling activity. It bundles actin filaments by formation of homodimers and binding to F-actin, making ITPKA to an important regulator of spine morphology.…”

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confidence: 99%

“…1 In these cells expression of ITPKA increases during brain development 1 and is highest in mature neurons, where the protein accumulates in dendritic spines. 2 Through conversion of inositol-1,4,5-trisphosphate (InsP 3 ) to inositol-1,3,4,5-tetrakisphosphate (InsP 4 ) ITPKA is an important regulator of InsP 3 induced calcium signaling in dendritic spines. 2,3 In addition to this catalytic activity, it has been shown that ITPKA has Factin bundling activity.…”

mentioning

confidence: 99%

“…2 Through conversion of inositol-1,4,5-trisphosphate (InsP 3 ) to inositol-1,3,4,5-tetrakisphosphate (InsP 4 ) ITPKA is an important regulator of InsP 3 induced calcium signaling in dendritic spines. 2,3 In addition to this catalytic activity, it has been shown that ITPKA has Factin bundling activity. It bundles actin filaments by formation of homodimers and binding to F-actin, making ITPKA to an important regulator of spine morphology.…”

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confidence: 99%

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Functional role of inositol‐1,4,5‐trisphosphate‐3‐kinase‐A for motility of malignant transformed cells

Windhorst

Kalinina

Schmid

et al. 2011

Intl Journal of Cancer

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Cell migration is one of the hallmarks of metastatic disease and thus identification of migration promoting proteins is crucial for the understanding of metastasis formation. Here we show that the neuron-specific, F-actin bundling inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) is ectopically expressed in tumor cells and critically involved in migration. Down-regulation of ITPKA expression in transformed cell-lines with ectopic expression of ITPKA significantly decreased migration and the number of linear and branched cell protrusion. Conversely, up-regulation of ITPKA in tumor cell lines with low endogenous ITPKA expression increased migration and formation of cell processes. In vitro, ITPKA alone induced the formation of linear actin filaments, whereas ITPKA mediated formation of branched protrusions seems to result from interaction between ITPKA and the F-actin cross-linking protein filamin C. Based on these actin-modulating and migration-promoting effects of ITPKA we examined its expression in clinical samples of different tumor entities, starting with the analysis of multiple tumor tissue arrays. As in lung adenocarcinoma specimens, the highest ITPKA expression rate was found, this tumor entity was examined in more detail. ITPKA was expressed early in adenocarcinoma progression (pN0) and was largely maintained in invasive and metastatic tumor cell populations (pN1/2, lymph node metastases). Together with our result that high expression of ITPKA increases motility of tumor cells we conclude that the observed expression of ITPKA early in tumor development increases the metastatic potential of lung adenocarcinoma cells. Therefore, we suggest that ITPKA may be a promising therapeutic molecular target for anti metastatic therapy of lung cancer.Under physiological conditions, inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA, GeneAtlas, V133A gcma, BioGPS, http:// biogps.gnf.org/#goto¼genereport&id¼3706) is only expressed in hippocampal, cortical and cerebellar neurons.1 In these cells expression of ITPKA increases during brain development 1 and is highest in mature neurons, where the protein accumulates in dendritic spines.2 Through conversion of inositol-1,4,5-trisphosphate (InsP 3 ) to inositol-1,3,4,5-tetrakisphosphate (InsP 4 ) ITPKA is an important regulator of InsP 3 induced calcium signaling in dendritic spines. 2,3 In addition to this catalytic activity, it has been shown that ITPKA has Factin bundling activity. It bundles actin filaments by formation of homodimers and binding to F-actin, making ITPKA to an important regulator of spine morphology. 4 Beside this physiological role, we recently have found a pathological function of ITPKA in tumor cells. We revealed that particular tumor cell lines express ITPKA and demonstrated that this ectopic expression of ITPKA increased the metastatic potential of tumor cells. Because of its F-actin bundling activity, ITPKA induces the formation of filopodia-and lamellipodia-like protrusions, 5,6 which are critical for cells to migrate. 7 This nonenzymatic migration-prom...

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“…InsP 3 -kinase-A (ITPKA) activity phosphorylates the calcium-mobilizing second messenger D-myo-inositol-1,4,5-trisphosphate [Ins (1,4,5)P 3 ] to D-myo-inositol-1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P 4 ] and thus is involved in the regulation of calcium signaling (1). Under physiologic conditions, ITPKA is expressed only in neurons of the hippocampus, neocortex, and cerebellum (GeneAtlas, V133A gcma, BioGPS; ref.…”

Section: Introductionmentioning

confidence: 99%

Expression Regulation of the Metastasis-Promoting Protein InsP3-Kinase-A in Tumor Cells

Chang

Schwarzenbach

Meyer-Staeckling

et al. 2011

Molecular Cancer Research

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Under physiologic conditions, the inositol-1,4,5-trisphosphate (InsP 3 )-metabolizing, F-actin-bundling InsP 3 -kinase-A (ITPKA) is expressed only in neurons. Tumor cells that have gained the ability to express ITPKA show an increased metastatic potential due to the migration-promoting properties of ITPKA. Here we investigated the mechanism how tumor cells have gained the ability to reexpress ITPKA by using a breast cancer cell line (T47D) with no expression and a lung carcinoma cell line (H1299) with ectopic ITPKA expression. Cloning of a 1,250-bp ITPKA promoter fragment revealed that methylation of CpG islands was reduced in H1299 as compared with T47D cells, but DNA demethylation did not alter the expression of ITPKA. Instead, we showed that the repressor-element-1-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), which suppresses expression of neuronal genes in nonneuronal tissues, regulates expression of ITPKA. Knockdown of REST/NRSF induced expression of ITPKA in T47D cells, whereas its overexpression in H1299 cells strongly reduced the level of ITPKA. In T47D cells, REST/NRSF was bound to the RE-1 site of the ITPKA promoter and strongly reduced its activity. In H1299 cells, in contrast, expressing comparable REST/NRSF levels as T47D cells, REST/NRSF only slightly reduced ITPKA promoter activity. This reduced suppressor activity most likely results from expression of a dominant-negative isoform of REST/NRSF, REST4, which impairs binding of REST/NRSF to the RE-1 site. Thus, ITPKA may belong to the neuronal metastasis-promoting proteins whose ectopic reexpression in tumor cells is associated with impaired REST/NRSF activity. Mol Cancer Res; 9(4); 497-506. Ó2011 AACR.

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

Cited by 33 publications

References 212 publications

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

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

Functional role of inositol‐1,4,5‐trisphosphate‐3‐kinase‐A for motility of malignant transformed cells

Expression Regulation of the Metastasis-Promoting Protein InsP3-Kinase-A in Tumor Cells

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