The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from ...The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes.Increasing evidence has implicated the dysregulation of STIM-ORAI and IP_3Rs in tumorigenesis and tumor progression.By controlling the activities,structure,and/or expression levels of these Ca^(2+)-transporting proteins,malignant cancer cells can hijack them to drive essential biological functions for tumor development.However,the molecular mechanisms underlying the participation of STIM-ORAI and IP_3Rs in the biological behavior of cancer remain elusive.In this review,we summarize recent advances regarding STIM-ORAI and IP_3Rs and discuss how they promote cell proliferation,apoptosis evasion,and cell migration through temporal and spatial rearrangements in certain types of malignant cells.An understanding of the essential roles of STIM-ORAI and IP_3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.展开更多
14-3-3 proteins play an important role in the regulation of many cellular processes. The Arabidopsis vacuolar two-pore K＋ channel 1 （TPK1） interacts with the 14-3-3 protein GRF6 （GF14-λ）. Upon phosphorylation of...14-3-3 proteins play an important role in the regulation of many cellular processes. The Arabidopsis vacuolar two-pore K＋ channel 1 （TPK1） interacts with the 14-3-3 protein GRF6 （GF14-λ）. Upon phosphorylation of the putative binding motif in the N-terminus of TPK1, GRF6 binds to TPK1 and activates the potassium channel. In order to gain a deeper understanding of this 14-3-3-mediated signal transduction, we set out to identify the respective kinases, which regulate the phosphorylation status of the 14-3-3 binding motif in TPK1. Here, we report that the calcium-dependent protein kinases （CDPKs） can phosphorylate and thereby activate the 14-3-3 binding motif in TPK1. Focusing on the stress-activated kinase CPK3, we visualized direct and specific interaction of TPK1 with the kinase at the tonoplast in vivo. In line with its proposed role in K＋ homeostasis, TPK1 phosphorylation was found to be induced by salt stress in planta, and both cpk3 and tpkl mutants displayed salt-sensitive phenotypes. Molecular modeling of the TPK1-CPK3 interaction domain provided mechanistic insights into TPK1 stress-regulated phosphorylation responses and pinpointed two arginine residues in the N-terminal 14-3-3 binding motif in TPK1 critical for kinase interaction. Taken together, our studies provide evidence for an essential role of the vacuolar potassium channel TPK1 in salt-stress adaptation as a target of calcium-regulated stress signaling pathways involving Ca2＋, Ca2＋-dependent kinases, and 14-3-3 proteins.展开更多
目的:研究内皮素-1(ET-1)诱导心肌肥大的机制及对抗的药物。方法:在培养新生大鼠心肌细胞中,采用L-型钙通道阻滞剂拉西地平(larc id ip ine)和MN9202、钙激活氯通道阻断剂尼氟灭酸(n iflum ic ac id,NFA)、蛋白激酶C(prote in k inase C...目的:研究内皮素-1(ET-1)诱导心肌肥大的机制及对抗的药物。方法:在培养新生大鼠心肌细胞中,采用L-型钙通道阻滞剂拉西地平(larc id ip ine)和MN9202、钙激活氯通道阻断剂尼氟灭酸(n iflum ic ac id,NFA)、蛋白激酶C(prote in k inase C,PKC)通路的阻断剂白屈菜季氨碱(chelerythrine,che)和ERK通路阻断剂PD98059(PD)观察内皮素-1在诱导心肌蛋白质合成中的影响。结果:对照组(DMEM)蛋白质含量为273±20μg/m l,ET-1组为312±30μg/m l,较对照组升高14%。ET-1+NFA组、ET-1+che组、ET-1+MN9202组、ET-1+larc id ip ine组、ET-1+PD98059组分别为280±10μg/m l、283±10μg/m l、285±27μg/m l、275±22μg/m l、293±33μg/m l;与ET-1组比较分别降低10%、9%、8.6%、13.1%、6.1%。结论:ET-1刺激引起的心肌细胞蛋白合成与钙激活氯通道和L-型钙通道有关,PKC和ERK通路在ET-1诱导心肌肥大的信号转导通路中起重要作用。展开更多
文摘The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes.Increasing evidence has implicated the dysregulation of STIM-ORAI and IP_3Rs in tumorigenesis and tumor progression.By controlling the activities,structure,and/or expression levels of these Ca^(2+)-transporting proteins,malignant cancer cells can hijack them to drive essential biological functions for tumor development.However,the molecular mechanisms underlying the participation of STIM-ORAI and IP_3Rs in the biological behavior of cancer remain elusive.In this review,we summarize recent advances regarding STIM-ORAI and IP_3Rs and discuss how they promote cell proliferation,apoptosis evasion,and cell migration through temporal and spatial rearrangements in certain types of malignant cells.An understanding of the essential roles of STIM-ORAI and IP_3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.
基金the Austrian Science Foundation (FWF) to M.T.，grants of the DFG to R.H.，T.D.M.，D.B.
文摘14-3-3 proteins play an important role in the regulation of many cellular processes. The Arabidopsis vacuolar two-pore K＋ channel 1 （TPK1） interacts with the 14-3-3 protein GRF6 （GF14-λ）. Upon phosphorylation of the putative binding motif in the N-terminus of TPK1, GRF6 binds to TPK1 and activates the potassium channel. In order to gain a deeper understanding of this 14-3-3-mediated signal transduction, we set out to identify the respective kinases, which regulate the phosphorylation status of the 14-3-3 binding motif in TPK1. Here, we report that the calcium-dependent protein kinases （CDPKs） can phosphorylate and thereby activate the 14-3-3 binding motif in TPK1. Focusing on the stress-activated kinase CPK3, we visualized direct and specific interaction of TPK1 with the kinase at the tonoplast in vivo. In line with its proposed role in K＋ homeostasis, TPK1 phosphorylation was found to be induced by salt stress in planta, and both cpk3 and tpkl mutants displayed salt-sensitive phenotypes. Molecular modeling of the TPK1-CPK3 interaction domain provided mechanistic insights into TPK1 stress-regulated phosphorylation responses and pinpointed two arginine residues in the N-terminal 14-3-3 binding motif in TPK1 critical for kinase interaction. Taken together, our studies provide evidence for an essential role of the vacuolar potassium channel TPK1 in salt-stress adaptation as a target of calcium-regulated stress signaling pathways involving Ca2＋, Ca2＋-dependent kinases, and 14-3-3 proteins.
文摘目的:研究内皮素-1(ET-1)诱导心肌肥大的机制及对抗的药物。方法:在培养新生大鼠心肌细胞中,采用L-型钙通道阻滞剂拉西地平(larc id ip ine)和MN9202、钙激活氯通道阻断剂尼氟灭酸(n iflum ic ac id,NFA)、蛋白激酶C(prote in k inase C,PKC)通路的阻断剂白屈菜季氨碱(chelerythrine,che)和ERK通路阻断剂PD98059(PD)观察内皮素-1在诱导心肌蛋白质合成中的影响。结果:对照组(DMEM)蛋白质含量为273±20μg/m l,ET-1组为312±30μg/m l,较对照组升高14%。ET-1+NFA组、ET-1+che组、ET-1+MN9202组、ET-1+larc id ip ine组、ET-1+PD98059组分别为280±10μg/m l、283±10μg/m l、285±27μg/m l、275±22μg/m l、293±33μg/m l;与ET-1组比较分别降低10%、9%、8.6%、13.1%、6.1%。结论:ET-1刺激引起的心肌细胞蛋白合成与钙激活氯通道和L-型钙通道有关,PKC和ERK通路在ET-1诱导心肌肥大的信号转导通路中起重要作用。
