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Placing ion channels into a signaling network of T cells: from maturing thymocytes to healthy T lymphocytes or leukemic T lymphoblasts.

Dobrovinskaya O, Delgado-Enciso I, Quintero-Castro LJ, Best-Aguilera C, Rojas-Sotelo RM, Pottosin I - Biomed Res Int (2015)

Bottom Line: A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially.In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death.In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Research, University of Colima, 28045 Colima, COL, Mexico.

ABSTRACT
T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility.

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Related in: MedlinePlus

K+ channels and their partners in the plasma membrane of T-cells. (a) Kv1.3 channels are activated and inactivated by the membrane depolarization. Its cytosolic N terminus binds to auxiliary, NADP binding β-subunit Kvβ2, possessing oxidoreductase activity, and sensing cell metabolism and redox state. It also mediates trafficking of members of Kv1 subfamily to plasma membrane. Beta-subunit via multifunctional adapter protein ZIP is linked to p56Lck, phosphotyrosine kinase in a phosphotyrosine-independent way. ZIP regulates a variety of intracellular processes as indicated. In turn, p56Lck is connected via PDZ-domain (hDlg) to the last three residues at the C-terminus; binding of hDlg to a kinesin motor protein (GAKIN) and provoking cortical cytoskeleton reorganization. Open state Kv1.3 conformation favors its binding to β1-integrin and the latter via integrin cytoplasmic domain associated protein (ICAP1-1a) and nucleoside diphosphate kinase NDPK-B (activating KCa3.1 via phosphorylation) communicates to intermediate conductance Ca2+-activated K+ channel KCa3.1 (substituted for small conductance KCa2.2 in Jurkat cells). Kv1.3 can promote clustering of all aforementioned interacting proteins plus CD4 in the immunological synapse. A colocalization of Kv1.3, KCa3.1, and CRAC channels is essential for synapse stability, via local K+ (K+ accumulation in the cleft, membrane depolarization) and Ca2+ signaling (for a further discussion, see [127]). Linking of Kv1.3 to integrin allows a bidirectional signaling, when K+ channel gating transmits to cell adhesion (inside-out signaling) and, vice versa, integrin-mediated external signal (outside-in) may be traduced to intracellular events via Kv1.3 and its interacting proteins. (b) hERG1 channels physically interact with β1-integrin receptors and are concentrated in caveolas, a type of lipid rafts, enriched of caveolins. Binary complexes of hERG1 with β1-integrin are typical for cancer cells. “Outside-in” signaling: hERG1 activation links β1-integrin adhesion to fibronectin (in the extracellular matrix, ECM) to the tyrosine phosphorylation of FAK and activation of small GTPase (Rac); both are coprecipitated with the channel protein. Caveolin association with β1-integrin promotes the channel activation [132]. FAK and ILK are primary targets for integrin-mediated cell adhesion, which transmits to the activation of MAPK, PI3K, and small GTPases. In leukemias trimolecular complexes can be also formed. In AML the third partner may be VEGF receptor, with an autocrine (hERG1-dependent) mechanism via VEGF secretion [133]. In ALL cells, hERG1/β1-integrin complex interacts with 7-TM domain (CXCR4, chemokine) receptors, stimulating signaling via ILK to Akt. Activation of this complex can be achieved via integrin engagement or CXCR4 chemical activation; ILK activity is suppressed by hERG1 specific block [134]. FAK (focal adhesion kinase), PI3K (phosphoinositide-3 kinase), VEGF (vascular endothelial growth factor), ILK (integrin linked kinase), and Akt (protein kinase B). (c) Tandem-pore domain K+ channel TRESK is activated by dephosphorylation by calcineurin (Cn) and suppressed by a phosphorylation of certain serine residues within the cytosolic loop between transmembrane domains II and III by protein kinase A (PKA) and a second kinase, likewise MARK, or microtubule affinity-regulating kinase [135]. Cn is activated either directly by Ca2+, Ca2+-CaM, or Ca2+-CaM-dependent kinase. Ca2+ influx in T-cells is mainly mediated by CRAC. Thus, TRESK and CRAC potentiate the activity of each other: TRESK generates driving force for Ca2+ influx by CRAC via membrane hyperpolarization, and CRAC shifts TRESK phosphorylation status to the dephosphorylated active form via Ca2+-Cn. Sustained increase of Ca2+ via Cn dephosphorylates NFAT and allows its entrance through a nuclear pore, hence activating genes transcription. Both TRESK and NFAT contain a characteristic Cn-docking site (PQIVID for TRESK and PxIxIT for NFAT), thus coupling the Ca2+ signal positive feedback loop to genes expression via Cn activity. 14-3-3 protein docking to the phosphorylated S264 protects it from the dephosphorylation; additionally, 14-3-3 protein inhibits the second kinase.
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fig3: K+ channels and their partners in the plasma membrane of T-cells. (a) Kv1.3 channels are activated and inactivated by the membrane depolarization. Its cytosolic N terminus binds to auxiliary, NADP binding β-subunit Kvβ2, possessing oxidoreductase activity, and sensing cell metabolism and redox state. It also mediates trafficking of members of Kv1 subfamily to plasma membrane. Beta-subunit via multifunctional adapter protein ZIP is linked to p56Lck, phosphotyrosine kinase in a phosphotyrosine-independent way. ZIP regulates a variety of intracellular processes as indicated. In turn, p56Lck is connected via PDZ-domain (hDlg) to the last three residues at the C-terminus; binding of hDlg to a kinesin motor protein (GAKIN) and provoking cortical cytoskeleton reorganization. Open state Kv1.3 conformation favors its binding to β1-integrin and the latter via integrin cytoplasmic domain associated protein (ICAP1-1a) and nucleoside diphosphate kinase NDPK-B (activating KCa3.1 via phosphorylation) communicates to intermediate conductance Ca2+-activated K+ channel KCa3.1 (substituted for small conductance KCa2.2 in Jurkat cells). Kv1.3 can promote clustering of all aforementioned interacting proteins plus CD4 in the immunological synapse. A colocalization of Kv1.3, KCa3.1, and CRAC channels is essential for synapse stability, via local K+ (K+ accumulation in the cleft, membrane depolarization) and Ca2+ signaling (for a further discussion, see [127]). Linking of Kv1.3 to integrin allows a bidirectional signaling, when K+ channel gating transmits to cell adhesion (inside-out signaling) and, vice versa, integrin-mediated external signal (outside-in) may be traduced to intracellular events via Kv1.3 and its interacting proteins. (b) hERG1 channels physically interact with β1-integrin receptors and are concentrated in caveolas, a type of lipid rafts, enriched of caveolins. Binary complexes of hERG1 with β1-integrin are typical for cancer cells. “Outside-in” signaling: hERG1 activation links β1-integrin adhesion to fibronectin (in the extracellular matrix, ECM) to the tyrosine phosphorylation of FAK and activation of small GTPase (Rac); both are coprecipitated with the channel protein. Caveolin association with β1-integrin promotes the channel activation [132]. FAK and ILK are primary targets for integrin-mediated cell adhesion, which transmits to the activation of MAPK, PI3K, and small GTPases. In leukemias trimolecular complexes can be also formed. In AML the third partner may be VEGF receptor, with an autocrine (hERG1-dependent) mechanism via VEGF secretion [133]. In ALL cells, hERG1/β1-integrin complex interacts with 7-TM domain (CXCR4, chemokine) receptors, stimulating signaling via ILK to Akt. Activation of this complex can be achieved via integrin engagement or CXCR4 chemical activation; ILK activity is suppressed by hERG1 specific block [134]. FAK (focal adhesion kinase), PI3K (phosphoinositide-3 kinase), VEGF (vascular endothelial growth factor), ILK (integrin linked kinase), and Akt (protein kinase B). (c) Tandem-pore domain K+ channel TRESK is activated by dephosphorylation by calcineurin (Cn) and suppressed by a phosphorylation of certain serine residues within the cytosolic loop between transmembrane domains II and III by protein kinase A (PKA) and a second kinase, likewise MARK, or microtubule affinity-regulating kinase [135]. Cn is activated either directly by Ca2+, Ca2+-CaM, or Ca2+-CaM-dependent kinase. Ca2+ influx in T-cells is mainly mediated by CRAC. Thus, TRESK and CRAC potentiate the activity of each other: TRESK generates driving force for Ca2+ influx by CRAC via membrane hyperpolarization, and CRAC shifts TRESK phosphorylation status to the dephosphorylated active form via Ca2+-Cn. Sustained increase of Ca2+ via Cn dephosphorylates NFAT and allows its entrance through a nuclear pore, hence activating genes transcription. Both TRESK and NFAT contain a characteristic Cn-docking site (PQIVID for TRESK and PxIxIT for NFAT), thus coupling the Ca2+ signal positive feedback loop to genes expression via Cn activity. 14-3-3 protein docking to the phosphorylated S264 protects it from the dephosphorylation; additionally, 14-3-3 protein inhibits the second kinase.

Mentions: Comparison of the Kv1.3 channels density in human peripheral blood resting T cells [137, 138, 141, 153, 159–163] and Jurkat lymphoblasts [139, 147, 149, 164–167] gives mean values of 380 and 215 active Kv1.3 copies per cell, respectively. In activated T cells, depending on subpopulation, the number of Kv1.3 channels could increase, modestly or very significantly, up to 1800 copies per cell [153]. Taking an approximately 3-fold larger membrane surface in Jurkat lymphoblasts into account, the Kv1.3 density, expressed as number of channels per unit area, is substantially lower in Jurkat cells. Yet, bearing in mind a complex Kv1.3 regulation within a signalosome, with all or some of interacting proteins involved [140] one may wonder, should such regulation be equally or more important than just a variation of the Kv1.3 copies numbers. Signaling complex, presented in Figure 3(a), exists within an immunological synapse. Thus, in case of leukemic cells, another question is whether there are alternative regulatory proteins, which interact with Kv1.3 in these cells and what is the outcome of such interaction. Regulation of Kv1.3 by p56Lck kinase [164, 165] as well as a colocalization with TCR/CD3 [168] is preserved in Jurkat cells. We are not aware, however, of any evidence pro or contra the functional interaction of Kv1.3 with integrins in leukemic T cells. It should be noted that p56Lck kinase mediates oxygen sensing by Kv1.3; hypoxia is a common condition within a tumor tissue and tends to suppress the Kv1.3 channel activity, thus, T-cell proliferation under conditions of O2 deprivation [169]. Healthy human leucocytes and Jurkat cells express a second type of β-subunit, KCNE (1 to 5). KCNE 4 but not 2 physically interacts and substantially modifies the Kv1.3 gating, decreases the channel surface expression, and impairs channel's targeting to lipid rafts [170]. Upon Jurkat activation with fetal bovine serum (FBS), KCNEs 2 and 4 were upregulated, but the same KCNEs were downregulated upon Jurkat activation by PHA [171]. Voltage gating of Kv1.3 was differentially modulated by the lipid rafts disintegration in healthy T cells [138] and Jurkat cells [139], suggesting a different microenvironment.


Placing ion channels into a signaling network of T cells: from maturing thymocytes to healthy T lymphocytes or leukemic T lymphoblasts.

Dobrovinskaya O, Delgado-Enciso I, Quintero-Castro LJ, Best-Aguilera C, Rojas-Sotelo RM, Pottosin I - Biomed Res Int (2015)

K+ channels and their partners in the plasma membrane of T-cells. (a) Kv1.3 channels are activated and inactivated by the membrane depolarization. Its cytosolic N terminus binds to auxiliary, NADP binding β-subunit Kvβ2, possessing oxidoreductase activity, and sensing cell metabolism and redox state. It also mediates trafficking of members of Kv1 subfamily to plasma membrane. Beta-subunit via multifunctional adapter protein ZIP is linked to p56Lck, phosphotyrosine kinase in a phosphotyrosine-independent way. ZIP regulates a variety of intracellular processes as indicated. In turn, p56Lck is connected via PDZ-domain (hDlg) to the last three residues at the C-terminus; binding of hDlg to a kinesin motor protein (GAKIN) and provoking cortical cytoskeleton reorganization. Open state Kv1.3 conformation favors its binding to β1-integrin and the latter via integrin cytoplasmic domain associated protein (ICAP1-1a) and nucleoside diphosphate kinase NDPK-B (activating KCa3.1 via phosphorylation) communicates to intermediate conductance Ca2+-activated K+ channel KCa3.1 (substituted for small conductance KCa2.2 in Jurkat cells). Kv1.3 can promote clustering of all aforementioned interacting proteins plus CD4 in the immunological synapse. A colocalization of Kv1.3, KCa3.1, and CRAC channels is essential for synapse stability, via local K+ (K+ accumulation in the cleft, membrane depolarization) and Ca2+ signaling (for a further discussion, see [127]). Linking of Kv1.3 to integrin allows a bidirectional signaling, when K+ channel gating transmits to cell adhesion (inside-out signaling) and, vice versa, integrin-mediated external signal (outside-in) may be traduced to intracellular events via Kv1.3 and its interacting proteins. (b) hERG1 channels physically interact with β1-integrin receptors and are concentrated in caveolas, a type of lipid rafts, enriched of caveolins. Binary complexes of hERG1 with β1-integrin are typical for cancer cells. “Outside-in” signaling: hERG1 activation links β1-integrin adhesion to fibronectin (in the extracellular matrix, ECM) to the tyrosine phosphorylation of FAK and activation of small GTPase (Rac); both are coprecipitated with the channel protein. Caveolin association with β1-integrin promotes the channel activation [132]. FAK and ILK are primary targets for integrin-mediated cell adhesion, which transmits to the activation of MAPK, PI3K, and small GTPases. In leukemias trimolecular complexes can be also formed. In AML the third partner may be VEGF receptor, with an autocrine (hERG1-dependent) mechanism via VEGF secretion [133]. In ALL cells, hERG1/β1-integrin complex interacts with 7-TM domain (CXCR4, chemokine) receptors, stimulating signaling via ILK to Akt. Activation of this complex can be achieved via integrin engagement or CXCR4 chemical activation; ILK activity is suppressed by hERG1 specific block [134]. FAK (focal adhesion kinase), PI3K (phosphoinositide-3 kinase), VEGF (vascular endothelial growth factor), ILK (integrin linked kinase), and Akt (protein kinase B). (c) Tandem-pore domain K+ channel TRESK is activated by dephosphorylation by calcineurin (Cn) and suppressed by a phosphorylation of certain serine residues within the cytosolic loop between transmembrane domains II and III by protein kinase A (PKA) and a second kinase, likewise MARK, or microtubule affinity-regulating kinase [135]. Cn is activated either directly by Ca2+, Ca2+-CaM, or Ca2+-CaM-dependent kinase. Ca2+ influx in T-cells is mainly mediated by CRAC. Thus, TRESK and CRAC potentiate the activity of each other: TRESK generates driving force for Ca2+ influx by CRAC via membrane hyperpolarization, and CRAC shifts TRESK phosphorylation status to the dephosphorylated active form via Ca2+-Cn. Sustained increase of Ca2+ via Cn dephosphorylates NFAT and allows its entrance through a nuclear pore, hence activating genes transcription. Both TRESK and NFAT contain a characteristic Cn-docking site (PQIVID for TRESK and PxIxIT for NFAT), thus coupling the Ca2+ signal positive feedback loop to genes expression via Cn activity. 14-3-3 protein docking to the phosphorylated S264 protects it from the dephosphorylation; additionally, 14-3-3 protein inhibits the second kinase.
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Show All Figures
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fig3: K+ channels and their partners in the plasma membrane of T-cells. (a) Kv1.3 channels are activated and inactivated by the membrane depolarization. Its cytosolic N terminus binds to auxiliary, NADP binding β-subunit Kvβ2, possessing oxidoreductase activity, and sensing cell metabolism and redox state. It also mediates trafficking of members of Kv1 subfamily to plasma membrane. Beta-subunit via multifunctional adapter protein ZIP is linked to p56Lck, phosphotyrosine kinase in a phosphotyrosine-independent way. ZIP regulates a variety of intracellular processes as indicated. In turn, p56Lck is connected via PDZ-domain (hDlg) to the last three residues at the C-terminus; binding of hDlg to a kinesin motor protein (GAKIN) and provoking cortical cytoskeleton reorganization. Open state Kv1.3 conformation favors its binding to β1-integrin and the latter via integrin cytoplasmic domain associated protein (ICAP1-1a) and nucleoside diphosphate kinase NDPK-B (activating KCa3.1 via phosphorylation) communicates to intermediate conductance Ca2+-activated K+ channel KCa3.1 (substituted for small conductance KCa2.2 in Jurkat cells). Kv1.3 can promote clustering of all aforementioned interacting proteins plus CD4 in the immunological synapse. A colocalization of Kv1.3, KCa3.1, and CRAC channels is essential for synapse stability, via local K+ (K+ accumulation in the cleft, membrane depolarization) and Ca2+ signaling (for a further discussion, see [127]). Linking of Kv1.3 to integrin allows a bidirectional signaling, when K+ channel gating transmits to cell adhesion (inside-out signaling) and, vice versa, integrin-mediated external signal (outside-in) may be traduced to intracellular events via Kv1.3 and its interacting proteins. (b) hERG1 channels physically interact with β1-integrin receptors and are concentrated in caveolas, a type of lipid rafts, enriched of caveolins. Binary complexes of hERG1 with β1-integrin are typical for cancer cells. “Outside-in” signaling: hERG1 activation links β1-integrin adhesion to fibronectin (in the extracellular matrix, ECM) to the tyrosine phosphorylation of FAK and activation of small GTPase (Rac); both are coprecipitated with the channel protein. Caveolin association with β1-integrin promotes the channel activation [132]. FAK and ILK are primary targets for integrin-mediated cell adhesion, which transmits to the activation of MAPK, PI3K, and small GTPases. In leukemias trimolecular complexes can be also formed. In AML the third partner may be VEGF receptor, with an autocrine (hERG1-dependent) mechanism via VEGF secretion [133]. In ALL cells, hERG1/β1-integrin complex interacts with 7-TM domain (CXCR4, chemokine) receptors, stimulating signaling via ILK to Akt. Activation of this complex can be achieved via integrin engagement or CXCR4 chemical activation; ILK activity is suppressed by hERG1 specific block [134]. FAK (focal adhesion kinase), PI3K (phosphoinositide-3 kinase), VEGF (vascular endothelial growth factor), ILK (integrin linked kinase), and Akt (protein kinase B). (c) Tandem-pore domain K+ channel TRESK is activated by dephosphorylation by calcineurin (Cn) and suppressed by a phosphorylation of certain serine residues within the cytosolic loop between transmembrane domains II and III by protein kinase A (PKA) and a second kinase, likewise MARK, or microtubule affinity-regulating kinase [135]. Cn is activated either directly by Ca2+, Ca2+-CaM, or Ca2+-CaM-dependent kinase. Ca2+ influx in T-cells is mainly mediated by CRAC. Thus, TRESK and CRAC potentiate the activity of each other: TRESK generates driving force for Ca2+ influx by CRAC via membrane hyperpolarization, and CRAC shifts TRESK phosphorylation status to the dephosphorylated active form via Ca2+-Cn. Sustained increase of Ca2+ via Cn dephosphorylates NFAT and allows its entrance through a nuclear pore, hence activating genes transcription. Both TRESK and NFAT contain a characteristic Cn-docking site (PQIVID for TRESK and PxIxIT for NFAT), thus coupling the Ca2+ signal positive feedback loop to genes expression via Cn activity. 14-3-3 protein docking to the phosphorylated S264 protects it from the dephosphorylation; additionally, 14-3-3 protein inhibits the second kinase.
Mentions: Comparison of the Kv1.3 channels density in human peripheral blood resting T cells [137, 138, 141, 153, 159–163] and Jurkat lymphoblasts [139, 147, 149, 164–167] gives mean values of 380 and 215 active Kv1.3 copies per cell, respectively. In activated T cells, depending on subpopulation, the number of Kv1.3 channels could increase, modestly or very significantly, up to 1800 copies per cell [153]. Taking an approximately 3-fold larger membrane surface in Jurkat lymphoblasts into account, the Kv1.3 density, expressed as number of channels per unit area, is substantially lower in Jurkat cells. Yet, bearing in mind a complex Kv1.3 regulation within a signalosome, with all or some of interacting proteins involved [140] one may wonder, should such regulation be equally or more important than just a variation of the Kv1.3 copies numbers. Signaling complex, presented in Figure 3(a), exists within an immunological synapse. Thus, in case of leukemic cells, another question is whether there are alternative regulatory proteins, which interact with Kv1.3 in these cells and what is the outcome of such interaction. Regulation of Kv1.3 by p56Lck kinase [164, 165] as well as a colocalization with TCR/CD3 [168] is preserved in Jurkat cells. We are not aware, however, of any evidence pro or contra the functional interaction of Kv1.3 with integrins in leukemic T cells. It should be noted that p56Lck kinase mediates oxygen sensing by Kv1.3; hypoxia is a common condition within a tumor tissue and tends to suppress the Kv1.3 channel activity, thus, T-cell proliferation under conditions of O2 deprivation [169]. Healthy human leucocytes and Jurkat cells express a second type of β-subunit, KCNE (1 to 5). KCNE 4 but not 2 physically interacts and substantially modifies the Kv1.3 gating, decreases the channel surface expression, and impairs channel's targeting to lipid rafts [170]. Upon Jurkat activation with fetal bovine serum (FBS), KCNEs 2 and 4 were upregulated, but the same KCNEs were downregulated upon Jurkat activation by PHA [171]. Voltage gating of Kv1.3 was differentially modulated by the lipid rafts disintegration in healthy T cells [138] and Jurkat cells [139], suggesting a different microenvironment.

Bottom Line: A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially.In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death.In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Research, University of Colima, 28045 Colima, COL, Mexico.

ABSTRACT
T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility.

Show MeSH
Related in: MedlinePlus