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Gary D Gilliland - One of the best experts on this subject based on the ideXlab platform.
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activation mutations of human c kit resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor pkc412
Blood, 2005Co-Authors: Joseph D Growney, Doriano Fabbro, Jennifer J Clark, Jennifer Adelsperger, Richard Stone, James D Griffin, Gary D GillilandAbstract:Constitutively activated forms of the transmembrane receptor tyrosine kinase c-KIT have been associated with systemic mast Cell disease, acute myeloid leukemia, and gastrointestinal stromal tumors. Reports of the resistance of the kinase domain mutation D816V to the adenosine triphosphate (ATP)-competitive kinase inhibitor imatinib mesylate prompted us to characterize 14 c-KIT mutations reported in association with human hematologic malignancies for transforming activity in the murine Hematopoietic Cell Line Ba/F3 and for sensitivity to the tyrosine kinase inhibitor PKC412. Ten of 14 c-KIT mutations conferred interleukin 3 (IL-3)-independent growth. c-KIT D816Y and D816V transformed Cells were sensitive to PKC412 despite resistance to imatinib mesylate. In these Cells, PKC412, but not imatinib mesylate, inhibited autophosphorylation of c-KIT and activation of downstream effectors signal transducer and transcriptional activator 5 (Stat5) and Stat3. Variable sensitivities to PKC412 or imatinib mesylate were observed among other mutants. These findings suggest that PKC412 may be a useful therapeutic agent for c-KIT-positive malignancies harboring the imatinib mesylate-resistant D816V or D816Y activation mutations.
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signal transduction and transforming properties of the tel trkc fusions associated with t 12 15 p13 q25 in congenital fibrosarcoma and acute myelogenous leukemia
The EMBO Journal, 2000Co-Authors: Gary D Gilliland, Qing Liu, Juerg Schwaller, Jeffery L Kutok, Danielle Cain, Jon C Aster, Ifor R WilliamsAbstract:The TEL–TRKC fusion is expressed as a consequence of t(12;15)(p13;q25), and is associated with two human cancers: congenital fibrosarcoma and acute myelogenous leukemia (AML). We report that the T/T(F) and T/T(L) fusion variants associated with congenital fibrosarcoma and AML, respectively, are constitutively tyrosine phosphorylated, and confer factor-independent growth to the murine Hematopoietic Cell Line Ba/F3. Retroviral transduction of T/T(L) causes a rapidly fatal myeloproliferative disease in a murine bone marrow transplant (BMT) model, whereas T/T(F) causes a long-latency, pre-B-Cell lymphoblastic lymphoma. TEL–TRKC variants are potent activators of the MAP kinase pathway, but neither variant activates Stat5 or other Stat family members. T/T(L), but not T/T(F), induces tyrosine phosphorylation of phospholipase Cγ (PLCγ), phosphoinositol-3 kinase and SHC. However, mutation analysis demonstrates that PLCγ tyrosine phos phorylation by T/T(L) is dispensable for induction of the myeloproliferative phenotype by T/T(L). Collectively, these data demonstrate that the TEL–TRKC fusion variants are oncoproteins that activate the MAP kinase pathway, and do not require activation of either PLCγ or Stat5 for efficient induction of a myeloproliferative phenotype in the murine BMT model.
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fusion of huntingtin interacting protein 1 to platelet derived growth factor β receptor pdgfβr in chronic myelomonocytic leukemia with t 5 7 q33 q11 2
Blood, 1998Co-Authors: Theodora S Ross, Olivier Bernard, Roland Berger, Gary D GillilandAbstract:We report the fusion of the Huntingtin interactin protein 1 (HIP1) gene to the platelet-derived growth factor betareceptor (PDGFbetaR) gene in a patient with chronic myelomonocytic leukemia (CMML) with a t(5;7)(q33;q11.2) translocation. Southern blot analysis of patient bone marrow Cells with a PDGFbetaR gene probe demonstrated rearrangement of the PDGFbetaR gene. Anchored polymerase chain reaction using PDGFbetaR primers identified a chimeric transcript containing the HIP1 gene located at 7q11.2 fused to the PDGFbetaR gene on 5q33. HIP1 is a 116-kD protein recently cloned by yeast two-hybrid screening for proteins that interact with Huntingtin, the mutated protein in Huntington's disease. The consequence of t(5;7)(q33;q11.2) is an HIP1/PDGFbetaR fusion gene that encodes amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFbetaR. The reciprocal PDGFbetaR/HIP1 transcript is not expressed. HIP1/PDGFbetaR is a 180-kD protein when expressed in the murine Hematopoietic Cell Line, Ba/F3, and is constitutively tyrosine phosphorylated. Furthermore, HIP1/PDGFbetaR transforms the Ba/F3 Cells to interleukin-3-independent growth. These data are consistent with an alternative mechanism for activation of PDGFbetaR tyrosine kinase activity by fusion with HIP1, leading to transformation of Hematopoietic Cells, and may implicate Huntingtin or HIP1 in the pathogenesis of Hematopoietic malignancies.
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the tel platelet derived growth factor β receptor pdgfβr fusion in chronic myelomonocytic leukemia is a transforming protein that self associates and activates pdgfβr kinase dependent signaling pathways
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Martin Carroll, Michael H Tomasson, G F Barker, Todd R Golub, Gary D GillilandAbstract:The TEL/PDGFβR fusion protein is the product of the t(5;12) translocation in patients with chronic myelomonocytic leukemia. The TEL/PDGFβR is an unusual fusion of a putative transcription factor, TEL, to a receptor tyrosine kinase. The translocation fuses the amino terminus of TEL, containing the helix-loop-helix (HLH) domain, to the transmembrane and cytoplasmic domain of the PDGFβR. We hypothesized that TEL/PDGFβR self-association, mediated by the HLH domain of TEL, would lead to constitutive activation of the PDGFβR tyrosine kinase domain and Cellular transformation. Analysis of in vitro-translated TEL/PDGFβR confirmed that the protein self-associated and that self-association was abrogated by deletion of 51 aa within the TEL HLH domain. In vivo, TEL/PDGFβR was detected as a 100-kDa protein that was constitutively phosphorylated on tyrosine and transformed the murine Hematopoietic Cell Line Ba/F3 to interleukin 3 growth factor independence. Transformation of Ba/F3 Cells required the HLH domain of TEL and the kinase activity of the PDGFβR portion of the fusion protein. Immunoblotting demonstrated that TEL/PDGFβR associated with multiple signaling molecules known to associate with the activated PDGFβR, including phospholipase C γ1, SHP2, and phosphoinositol-3-kinase. TEL/PDGFβR is a novel transforming protein that self-associates and activates PDGFβR-dependent signaling pathways. Oligomerization of TEL/PDGFβR that is dependent on the TEL HLH domain provides further evidence that the HLH domain, highly conserved among ETS family members, is a self-association motif.
Tadatsugu Taniguchi - One of the best experts on this subject based on the ideXlab platform.
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critical role of the interleukin 2 il 2 receptor gamma chain associated jak3 in the il 2 induced c fos and c myc but not bcl 2 gene induction
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Atsuo Kawahara, Yasuhiro Minami, Tadaaki Miyazaki, James N Ihle, Tadatsugu TaniguchiAbstract:The interleukin 2 receptor (IL-2R) consists of three subunits, the IL-2R alpha, IL-2R beta c, and IL-2R gamma c chains. Two Janus family protein tyrosine kinases (PTKs), Jak1 and Jak3, were shown to associate with IL-2R beta c and IL-2R gamma c, respectively, and their PTK activities are increased after IL-2 stimulation. A Jak3 mutant with truncation of the C-terminal PTK domain lacks its intrinsic kinase activity but can still associate with IL-2R gamma c. In a Hematopoietic Cell Line, F7, that responds to either IL-2 or IL-3, overexpression of this Jak3 mutant results in selective inhibition of the IL-2-induced activation of Jak1/Jak3 PTKs and of Cell proliferation. Of the three target nuclear protooncogenes of the IL-2 signaling, c-fos and c-myc genes, but not the bcl-2 gene, were found to be impaired. On the other hand, overexpression of the dominant negative form of the IL-2R gamma c chain, which lacks most of its cytoplasmic domain, in F7 Cells resulted in the inhibition of all three protooncogenes. These results provide a further molecular basis for the critical role of Jak3 in IL-2 signaling and also suggest a Jak PTK-independent signaling pathway(s) for the bcl-2 gene induction by IL-2R.
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protein tyrosine kinase syk is associated with and activated by the il 2 receptor possible link with the c myc induction pathway
Immunity, 1995Co-Authors: Yasuhiro Minami, Atsuo Kawahara, Yoko Nakagawa, Tadaski Miyazaki, Kiyonao Sada, Hirohei Yamamura, Tadatsugu TaniguchiAbstract:Abstract The IL-2 receptor (IL-2R) consists of three subunits, the IL-2Rα, IL-2Rβ, and IL-2Rγ chains. The IL-2-induced proliferative signals emanate from the cytoplasmic domains of IL-2Rβ and IL-2Rγ, but the nature and function of the signaling molecules that transmit these signals are not fully understood. Here, we report that Syk protein tyrosine kinase (PTK) Is physically associated with IL-2R in peripheral blood lymphocytes. cDNA expression studies further revealed that this association is critical for the IL-2-induced activation of Syk PTK, which occurs primarily via the serine-rich region of the IL-2Rβ chain, which is essential for proliferative signal transmission. Furthermore, we provide evidence that in the Hematopoietic Cell Line, BAF-B03, the activation of Syk PTK results in the induction of the c- myc gene, an event critical for the Cell proliferation. Thus, Syk PTK may be a critical integral member of the signaling molecules engaged by the IL-2R.
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evidence for a critical role for the cytoplasmic region of the interleukin 2 il 2 receptor gamma chain in il 2 il 4 and il 7 signalling
Molecular and Cellular Biology, 1994Co-Authors: Atsuo Kawahara, Yasuhiro Minami, Tadatsugu TaniguchiAbstract:The high-affinity interleukin 2 receptor (IL-2R) consists of at least three distinct subunits: the IL-2R alpha chain (IL-2R alpha), beta chain (IL-2R beta), and gamma chain (IL-2R gamma). It has been shown that the cytoplasmic region of IL-2R beta, but not of IL-2R alpha, is essential for IL-2 signalling to the Cell interior. In the present study, we examined the functional role of the IL-2R gamma cytoplasmic region in the IL-3-dependent mouse Hematopoietic Cell Line BAF-B03, which expresses the endogenous IL-2R alpha and IL-2R gamma, or its subLine F7, which additionally expresses human IL-2R beta cDNA. We show that overexpression of a mutant IL-2R gamma, lacking all but 7 amino acids of its cytoplasmic region, results in the selective inhibition of IL-2-induced c-fos gene activation and Cellular proliferation in F7 Cells. When two chimeric receptor molecules in which the cytoplasmic regions of IL-2R beta and IL-2R gamma had been swapped with each other (IL-2R beta/gamma and IL-2R gamma/beta) were coexpressed in BAF-B03, the Cells responded to IL-2. These results indicate the critical importance of the IL-2-induced functional cooperation of the two cytoplasmic regions. Finally, we provide evidence that the IL-2R gamma cytoplasmic region is also critical for the IL-4 and IL-7-induced growth signal transduction in BAF-B03.
John C Reed - One of the best experts on this subject based on the ideXlab platform.
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structure function analysis of the bcl 2 oncoprotein addition of a heterologous transmembrane domain to portions of the bcl 2 beta protein restores function as a regulator of Cell survival
Journal of Biological Chemistry, 1993Co-Authors: S Tanaka, K Saito, John C ReedAbstract:Abstract The bcl-2 gene can potentially encode 26- and 22-kDa proteins that differ only in their carboxyl tails because of an alternative splicing mechanism. The larger of these proteins contains a hydrophobic transmembrane domain within its carboxyl terminus, resides (at least in part) in mitochondrial membranes and has been shown to prolong Cell survival by blocking programmed Cell death (also termed "apoptosis"). To explore the function of the shorter 22-kDa Bcl-2 protein that lacks a transmembrane domain, DNAs encoding p26-Bcl-2-alpha or p22-Bcl-2-beta were expressed in an interleukin-3 (IL-3)-dependent Hematopoietic Cell Line 32D. In contrast to p26-Bcl-2 alpha that markedly prolonged Cell survival, p22-Bcl-2-beta did not extend the survival of 32D Cells when cultured in the absence of IL-3. Expression in 32D Cells of a chimeric DNA that fused portions of the open reading frame common to Bcl-2-alpha and Bcl-2-beta (amino-acids 1-195) with sequences encoding the transmembrane and cytosolic domains of the IL-2 receptor-alpha protein resulted in production of a Bcl-2/IL-2R fusion protein that was capable of prolonging 32D Cell survival in the setting of IL-3 withdrawal. Based on fractionation of Cells to produce crude heavy membrane, light membrane, nuclei, and cytosolic preparations, much of the p22-Bcl-2-beta protein appeared to reside in the cytosol, whereas Bcl-2-alpha and the Bcl-2/IL-2R chimeric proteins were found exclusively in fractions that also contained the inner mitochondrial membrane protein F1-beta-ATPase. Taken together, these findings demonstrate the importance of membrane association for the function and intraCellular targeting of the apoptosis-blocking Bcl-2 protein. Furthermore, despite the strong evolutionary conservation of the carboxyl regions of Bcl-2-alpha proteins observed previously for mammalian and avian species, these data suggest that a heterologous transmembrane domain can be substituted without loss of function.
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apoptosis induced by withdrawal of interleukin 3 il 3 from an il 3 dependent Hematopoietic Cell Line is associated with repartitioning of intraCellular calcium and is blocked by enforced bcl 2 oncoprotein production
Journal of Biological Chemistry, 1993Co-Authors: Gyorgy Baffy, T Miyashita, John R Williamson, John C ReedAbstract:Abstract The regulation of intraCellular pools of Ca2+ was investigated in an interleukin-3 (IL-3)-dependent Hematopoietic Cell Line 32D that undergoes programmed Cell death ("apoptosis") when deprived of lymphokine. Comparisons were made with 32D Cells that had been stably transfected with a bcl-2 expression plasmid that encodes a 26-kDa intraCellular integral-membrane protein known to abrogate apoptosis resulting from IL-3 withdrawal. Removal of IL-3 from cultures of 32D Cells or control-transfected 32D-NEO Cells for 1-2 days led to Cell cycle arrest and oligonucleosomal DNA fragmentation and was associated with lower cytosolic free Ca2+ concentrations ([Ca2+]i), as measured by Indo-1 fluorescence of viable Cells in Ca(2+)-containing media. In bcl-2-expressing 32D-BCL2 Cells, IL-3 withdrawal also resulted in cessation of proliferation, but [Ca2+]i levels were not decreased and DNA fragmentation was markedly suppressed. Nonmitochondrial stores of Ca2+ were also significantly diminished in IL-3-deprived 32D-NEO but not in 32D-BCL2 Cells, based on measurements of Ca2+ release into the cytosol following exposure of Cells to thapsigargin (an inhibitor of endoplasmic reticulum Ca(2+)-ATPases) under Ca(2+)-free conditions. In contrast, estimates of mitochondrial Ca2+ stores using an uncoupler of oxidative phosphorylation 1799 (2,6-dihydroxy-1,1,1,7,7,7-he xafluoro-2,6-bis(trifluoromethyl)heptan-4-one[bis(he xafluoroacetonyl)]acetone) suggested that IL-3 deprivation leads to an increase in this intraCellular pool of Ca2+ in 32D-NEO but not in 32D-BCL2 Cells. Re-addition of IL-3 to factor-deprived 32D-NEO Cells reversed the changes in thapsigargin- and 1799-releasable Ca2+ pools and rescued many of the Cells from death. Measurements of total Cellular Ca2+ revealed no difference in 32D-NEO Cells before and after IL-3 withdrawal, suggesting that the observed alterations in mitochondrial and nonmitochondrial Ca2+ pools result from intraCellular repartitioning of Ca2+. Treatment of IL-3-deprived 32D-NEO Cells with Ca2+ ionophores blocked DNA fragmentation and prolonged Cell survival, whereas addition of Ca2+ chelators to IL-3-stimulated 32D Cells resulted in oligonucleosomal DNA fragmentation and Cell death, suggesting that diminutions in the concentrations of Ca2+ in cytosol, endoplasmic reticulum, or other intraCellular compartments either directly or indirectly regulate apoptosis in these lymphokine-dependent Hematopoietic Cells.
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apoptosis induced by withdrawal of interleukin 3 il 3 from an il 3 dependent Hematopoietic Cell Line is associated with repartitioning of intraCellular calcium and is blocked by enforced bcl 2 oncoprotein production
Journal of Biological Chemistry, 1993Co-Authors: Gyorgy Baffy, T Miyashita, John R Williamson, John C ReedAbstract:The regulation of intraCellular pools of Ca2+ was investigated in an interleukin-3 (IL-3)-dependent Hematopoietic Cell Line 32D that undergoes programmed Cell death ("apoptosis") when deprived of lymphokine. Comparisons were made with 32D Cells that had been stably transfected with a bcl-2 expression plasmid that encodes a 26-kDa intraCellular integral-membrane protein known to abrogate apoptosis resulting from IL-3 withdrawal. Removal of IL-3 from cultures of 32D Cells or control-transfected 32D-NEO Cells for 1-2 days led to Cell cycle arrest and oligonucleosomal DNA fragmentation and was associated with lower cytosolic free Ca2+ concentrations ([Ca2+]i), as measured by Indo-1 fluorescence of viable Cells in Ca(2+)-containing media. In bcl-2-expressing 32D-BCL2 Cells, IL-3 withdrawal also resulted in cessation of proliferation, but [Ca2+]i levels were not decreased and DNA fragmentation was markedly suppressed. Nonmitochondrial stores of Ca2+ were also significantly diminished in IL-3-deprived 32D-NEO but not in 32D-BCL2 Cells, based on measurements of Ca2+ release into the cytosol following exposure of Cells to thapsigargin (an inhibitor of endoplasmic reticulum Ca(2+)-ATPases) under Ca(2+)-free conditions. In contrast, estimates of mitochondrial Ca2+ stores using an uncoupler of oxidative phosphorylation 1799 (2,6-dihydroxy-1,1,1,7,7,7-he xafluoro-2,6-bis(trifluoromethyl)heptan-4-one[bis(he xafluoroacetonyl)]acetone) suggested that IL-3 deprivation leads to an increase in this intraCellular pool of Ca2+ in 32D-NEO but not in 32D-BCL2 Cells. Re-addition of IL-3 to factor-deprived 32D-NEO Cells reversed the changes in thapsigargin- and 1799-releasable Ca2+ pools and rescued many of the Cells from death. Measurements of total Cellular Ca2+ revealed no difference in 32D-NEO Cells before and after IL-3 withdrawal, suggesting that the observed alterations in mitochondrial and nonmitochondrial Ca2+ pools result from intraCellular repartitioning of Ca2+. Treatment of IL-3-deprived 32D-NEO Cells with Ca2+ ionophores blocked DNA fragmentation and prolonged Cell survival, whereas addition of Ca2+ chelators to IL-3-stimulated 32D Cells resulted in oligonucleosomal DNA fragmentation and Cell death, suggesting that diminutions in the concentrations of Ca2+ in cytosol, endoplasmic reticulum, or other intraCellular compartments either directly or indirectly regulate apoptosis in these lymphokine-dependent Hematopoietic Cells.
Atsuo Kawahara - One of the best experts on this subject based on the ideXlab platform.
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critical role of the interleukin 2 il 2 receptor gamma chain associated jak3 in the il 2 induced c fos and c myc but not bcl 2 gene induction
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Atsuo Kawahara, Yasuhiro Minami, Tadaaki Miyazaki, James N Ihle, Tadatsugu TaniguchiAbstract:The interleukin 2 receptor (IL-2R) consists of three subunits, the IL-2R alpha, IL-2R beta c, and IL-2R gamma c chains. Two Janus family protein tyrosine kinases (PTKs), Jak1 and Jak3, were shown to associate with IL-2R beta c and IL-2R gamma c, respectively, and their PTK activities are increased after IL-2 stimulation. A Jak3 mutant with truncation of the C-terminal PTK domain lacks its intrinsic kinase activity but can still associate with IL-2R gamma c. In a Hematopoietic Cell Line, F7, that responds to either IL-2 or IL-3, overexpression of this Jak3 mutant results in selective inhibition of the IL-2-induced activation of Jak1/Jak3 PTKs and of Cell proliferation. Of the three target nuclear protooncogenes of the IL-2 signaling, c-fos and c-myc genes, but not the bcl-2 gene, were found to be impaired. On the other hand, overexpression of the dominant negative form of the IL-2R gamma c chain, which lacks most of its cytoplasmic domain, in F7 Cells resulted in the inhibition of all three protooncogenes. These results provide a further molecular basis for the critical role of Jak3 in IL-2 signaling and also suggest a Jak PTK-independent signaling pathway(s) for the bcl-2 gene induction by IL-2R.
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protein tyrosine kinase syk is associated with and activated by the il 2 receptor possible link with the c myc induction pathway
Immunity, 1995Co-Authors: Yasuhiro Minami, Atsuo Kawahara, Yoko Nakagawa, Tadaski Miyazaki, Kiyonao Sada, Hirohei Yamamura, Tadatsugu TaniguchiAbstract:Abstract The IL-2 receptor (IL-2R) consists of three subunits, the IL-2Rα, IL-2Rβ, and IL-2Rγ chains. The IL-2-induced proliferative signals emanate from the cytoplasmic domains of IL-2Rβ and IL-2Rγ, but the nature and function of the signaling molecules that transmit these signals are not fully understood. Here, we report that Syk protein tyrosine kinase (PTK) Is physically associated with IL-2R in peripheral blood lymphocytes. cDNA expression studies further revealed that this association is critical for the IL-2-induced activation of Syk PTK, which occurs primarily via the serine-rich region of the IL-2Rβ chain, which is essential for proliferative signal transmission. Furthermore, we provide evidence that in the Hematopoietic Cell Line, BAF-B03, the activation of Syk PTK results in the induction of the c- myc gene, an event critical for the Cell proliferation. Thus, Syk PTK may be a critical integral member of the signaling molecules engaged by the IL-2R.
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evidence for a critical role for the cytoplasmic region of the interleukin 2 il 2 receptor gamma chain in il 2 il 4 and il 7 signalling
Molecular and Cellular Biology, 1994Co-Authors: Atsuo Kawahara, Yasuhiro Minami, Tadatsugu TaniguchiAbstract:The high-affinity interleukin 2 receptor (IL-2R) consists of at least three distinct subunits: the IL-2R alpha chain (IL-2R alpha), beta chain (IL-2R beta), and gamma chain (IL-2R gamma). It has been shown that the cytoplasmic region of IL-2R beta, but not of IL-2R alpha, is essential for IL-2 signalling to the Cell interior. In the present study, we examined the functional role of the IL-2R gamma cytoplasmic region in the IL-3-dependent mouse Hematopoietic Cell Line BAF-B03, which expresses the endogenous IL-2R alpha and IL-2R gamma, or its subLine F7, which additionally expresses human IL-2R beta cDNA. We show that overexpression of a mutant IL-2R gamma, lacking all but 7 amino acids of its cytoplasmic region, results in the selective inhibition of IL-2-induced c-fos gene activation and Cellular proliferation in F7 Cells. When two chimeric receptor molecules in which the cytoplasmic regions of IL-2R beta and IL-2R gamma had been swapped with each other (IL-2R beta/gamma and IL-2R gamma/beta) were coexpressed in BAF-B03, the Cells responded to IL-2. These results indicate the critical importance of the IL-2-induced functional cooperation of the two cytoplasmic regions. Finally, we provide evidence that the IL-2R gamma cytoplasmic region is also critical for the IL-4 and IL-7-induced growth signal transduction in BAF-B03.
Yasuhiro Minami - One of the best experts on this subject based on the ideXlab platform.
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critical role of the interleukin 2 il 2 receptor gamma chain associated jak3 in the il 2 induced c fos and c myc but not bcl 2 gene induction
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Atsuo Kawahara, Yasuhiro Minami, Tadaaki Miyazaki, James N Ihle, Tadatsugu TaniguchiAbstract:The interleukin 2 receptor (IL-2R) consists of three subunits, the IL-2R alpha, IL-2R beta c, and IL-2R gamma c chains. Two Janus family protein tyrosine kinases (PTKs), Jak1 and Jak3, were shown to associate with IL-2R beta c and IL-2R gamma c, respectively, and their PTK activities are increased after IL-2 stimulation. A Jak3 mutant with truncation of the C-terminal PTK domain lacks its intrinsic kinase activity but can still associate with IL-2R gamma c. In a Hematopoietic Cell Line, F7, that responds to either IL-2 or IL-3, overexpression of this Jak3 mutant results in selective inhibition of the IL-2-induced activation of Jak1/Jak3 PTKs and of Cell proliferation. Of the three target nuclear protooncogenes of the IL-2 signaling, c-fos and c-myc genes, but not the bcl-2 gene, were found to be impaired. On the other hand, overexpression of the dominant negative form of the IL-2R gamma c chain, which lacks most of its cytoplasmic domain, in F7 Cells resulted in the inhibition of all three protooncogenes. These results provide a further molecular basis for the critical role of Jak3 in IL-2 signaling and also suggest a Jak PTK-independent signaling pathway(s) for the bcl-2 gene induction by IL-2R.
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protein tyrosine kinase syk is associated with and activated by the il 2 receptor possible link with the c myc induction pathway
Immunity, 1995Co-Authors: Yasuhiro Minami, Atsuo Kawahara, Yoko Nakagawa, Tadaski Miyazaki, Kiyonao Sada, Hirohei Yamamura, Tadatsugu TaniguchiAbstract:Abstract The IL-2 receptor (IL-2R) consists of three subunits, the IL-2Rα, IL-2Rβ, and IL-2Rγ chains. The IL-2-induced proliferative signals emanate from the cytoplasmic domains of IL-2Rβ and IL-2Rγ, but the nature and function of the signaling molecules that transmit these signals are not fully understood. Here, we report that Syk protein tyrosine kinase (PTK) Is physically associated with IL-2R in peripheral blood lymphocytes. cDNA expression studies further revealed that this association is critical for the IL-2-induced activation of Syk PTK, which occurs primarily via the serine-rich region of the IL-2Rβ chain, which is essential for proliferative signal transmission. Furthermore, we provide evidence that in the Hematopoietic Cell Line, BAF-B03, the activation of Syk PTK results in the induction of the c- myc gene, an event critical for the Cell proliferation. Thus, Syk PTK may be a critical integral member of the signaling molecules engaged by the IL-2R.
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evidence for a critical role for the cytoplasmic region of the interleukin 2 il 2 receptor gamma chain in il 2 il 4 and il 7 signalling
Molecular and Cellular Biology, 1994Co-Authors: Atsuo Kawahara, Yasuhiro Minami, Tadatsugu TaniguchiAbstract:The high-affinity interleukin 2 receptor (IL-2R) consists of at least three distinct subunits: the IL-2R alpha chain (IL-2R alpha), beta chain (IL-2R beta), and gamma chain (IL-2R gamma). It has been shown that the cytoplasmic region of IL-2R beta, but not of IL-2R alpha, is essential for IL-2 signalling to the Cell interior. In the present study, we examined the functional role of the IL-2R gamma cytoplasmic region in the IL-3-dependent mouse Hematopoietic Cell Line BAF-B03, which expresses the endogenous IL-2R alpha and IL-2R gamma, or its subLine F7, which additionally expresses human IL-2R beta cDNA. We show that overexpression of a mutant IL-2R gamma, lacking all but 7 amino acids of its cytoplasmic region, results in the selective inhibition of IL-2-induced c-fos gene activation and Cellular proliferation in F7 Cells. When two chimeric receptor molecules in which the cytoplasmic regions of IL-2R beta and IL-2R gamma had been swapped with each other (IL-2R beta/gamma and IL-2R gamma/beta) were coexpressed in BAF-B03, the Cells responded to IL-2. These results indicate the critical importance of the IL-2-induced functional cooperation of the two cytoplasmic regions. Finally, we provide evidence that the IL-2R gamma cytoplasmic region is also critical for the IL-4 and IL-7-induced growth signal transduction in BAF-B03.