IL—18信号转导途径研究进展

白细胞介素１８（ＩＬ－１８）是新近发现的细胞因子,其独特的少ＴＡＴＡ型启动子、特殊的ｍＲＮＡ结构及其前体蛋白需ＩＬ－１β转化酶（ＩＣＥ）加工成熟的特点,便得ＩＬ－１８基因可广泛表达于多种类型的细胞,ＩＬ－１８ＩＬ－１８受体结合组成受体复合物,受体复合物信号通过ＩＲＡＫ－ＴＲＡＦ６途径激活ＮＦ－кＢ,及通过酪氨酸蛋白激酶（ＰＴＫ）的ＬＣＫ－ＭＡＰＫ信号途径诱导ＴＨ１细胞产生ＩＦＮ－γ、ＩＬ－２等细胞     

BCR信号转导研究进展

Ｂ细胞表面抗原受体（ＢＣＲ）与其抗原或其它配体（如ａｎｔｉ－μＭｃＡｂ）的结合启动了Ｂ细胞的活化,ＢＣＲ交联后,首先在其ＩＴＡＭ序列部位发生酪氨酸磷酸化,从而富集并激活Ｓｒｃ家族蛋白质酪氨酸激酶（ＰＴＫ）,进而Ｓｒｃ家族ＰＴＫ将ＳｙｋＰＴＫ等的酪氨酸磷化而活化,使信号传递下去,在此过程中,还有ＦｏｒγＲⅡｂ和ＣＤ２２等分子通过富集蛋白质酪氨酸磷酸酶ＰＴＰＩＣ活化信号进行负调控,本文就此ＢＣＲ信号转     

Ras蛋白与信号传导

Ｒａｓ介导的信号传导途径是近几年研究热点之一,这是因为许多细胞受体介导的信号通路和Ｒａｓ途径相关。Ｒａｓ蛋白广泛存在生物界,在信号传导途径中起着极为重要的开关作用。ＰＴＫ、Ｒａｓ、Ｒａｆ、ＭＡＰＫＫ和ＭＡＰＫ通过复杂的蛋白与蛋白之间的相互作用以及蛋白质磷酸化,将外界信号传入细胞中从而对细胞生长产生影响。本文对Ｒａｓ介导的信号传导途径的最新研究近展进行综述。     

细胞分裂素结合蛋白的研究进展

迄今为止,已从多种植物中分离到细胞分裂素结合蛋白（ＣＢＰｓ）,它们可能在细胞分裂素的信号转导、体内运输及代谢中起作用。根据现有研究结果认为,大多数ＣＴＫｓ受体可能位于膜上,通过与Ｇ－蛋白耦联的信号转导系统或双组分信号转导系统完成ＣＴＫｓ信号的跨膜转导。少数ＣＴＫｓ受体可能位于细胞质中,与胞内ＣＴＫｓ结合后进入细胞核,直接调节基因的表达。本文综述了近年来对ＣＢＰｓ的研究进展,分析了ＣＴＫｓ受体的可能     

植物富含亮氨酸重复序列型类受体蛋白激酶的生物学功能

介绍了植物富含亮氨酸重复序列(leucine-rich repeat,LRR)型类受体蛋白激酶概念、最近发现的这类蛋白激酶的亚结构域特征;总结了目前已确定其功能的LRR型类受体蛋白激酶,并分别阐述了它们在参与植物抗逆性反应、发育调控及激素的信号转导等过程中的生物学功能;着重介绍和讨论了LRR型类受体蛋白激酶复合物之间及其与下游成分KAPP之间互作而产生信号传递的分子机理.最后展望了LRR型类受体蛋白激酶生物学功能、信号转导机制、以及应用于生产实践的研究前景.     

T细胞活化的跨膜接头蛋白

Ｔ细胞通过抗原受体 (ＴＣＲ)识别抗原后 ,经ＣＤ3分子激活多种蛋白酪氨酸激酶 (ＰＴＫ)和胞质接头蛋白 ,从而活化一系列胞质激酶 ,如磷脂酰肌醇 3激酶 (ＰＩ3Ｋ)、磷脂酶Ｃγ(ＰＬＣγ)、Ｒａｓ激酶等 ,再经一系列信号传递激活转录因子调节基因表达 ,使细胞表现功能。最近发现了一组ＴＣＲ相关的跨膜接头蛋白 ,包括Ｔ细胞活化的连接分子 (ｌｉｎｋｅｒｆｏｒａｃｔｉｖａ ｔｉｏｎｏｆＴｃｅｌｌｓ,ＬＡＴ)、ＳＨＰ2相互作用跨膜接头蛋白 (ＳＨＰ2 ｉｎｔｅｒａｃｔｉｎｇｔｒａｎｓｍｅｍｂｒａｎｅａｄａｐｔｏｒｐｒｏｔｅｉｎ ,ＳＩＴ…     

NMDA受体信号复合体中蛋白质的相互作用

谷氨酸能兴奋性突触的突触后密集区(postsynaptic density,PSD)包含多种受体蛋白、骨架蛋白和信号蛋白,它们通过分子中特定的结构域相互识别并动态地结合,形成多个信号复合体,参与突触后受体功能的调节及其下游特异性信号转导通路的激活。其中,NMDA受体信号复合体中蛋白质-蛋白质的相互作用及其调控机制的阐明,对于深入了解神经发育、突触可塑性、兴奋性毒性等生理病理的分子机制有重要意义。     

细胞因子信号的部分负调控因子

免疫和造血细胞的生长、分化及其他功能受到细胞因子网络的控制。由于大多数细胞因子受体缺乏胞浆段的激酶结构域 ,配体依赖的酪氨酸磷酸化由非受体酪氨酸激酶来中介。细胞因子刺激后早期激活的主要酪氨酸激酶是Ｊａｎｕｓｋｉｎａｓｅ(ＪＡＫ)家族。事实上 ,ＪＡＫ ＳＴＡＴ途径是许多细胞因子激活基因转录最重要机制之一。当细胞因子结合到细胞表面的受体 ,引起受体的二聚化 ,进而活化ＪＡＫ激酶 ,活化的ＪＡＫ激酶反过来磷酸化细胞因子受体 ,导致其他的信号分子如ＳＴＡＴ家族蛋白的介入并被激活 ,活化的ＳＴＡＴ转入细胞核 ,激活大量细…     

雌激素信号通路概述

过去几十年,人们一直认为雌激素信号通路是雌激素与细胞核中的雌激素受体(ER)结合,作用于雌激素受体反应元件调节基因表达,从而改变细胞功能。雌激素不但与核ER结合,也能与膜ER结合激活PI3K信号通路。G蛋白偶联受体(GPR30)也能与雌激素结合,激活PI3K信号通路。雌激素通过结合不同雌激素受体改变细胞生理功能。我们对雌激素信号通路做简要综述。     

转化生长因子-β族信号的转导

TGF-β族细胞因子通过各自信号转导产生多种生物学效应,其基本过程是：信号沿TGF-β族配体→受体→SMAD蛋白→转录因子→DNA表达的次序转导.在TGF-β族各因子刺激各自具有蛋白激酶活性的两型膜受体时,各因子先结合Ⅱ型受体,结合配体的Ⅱ型受体再激活Ⅰ型受体.活化的I型受体磷酸化通路特异性SMAD,后者与公用性SMAD结合后从胞浆移至核内,核内SMAD通过与转录因子结合和直接与DNA结合调节基因的表达.     

Janus kinase (Jak) subcellular localization revisited: the exclusive membrane localization of endogenous Janus kinase 1 by cytokine receptor interaction uncovers the Jak.receptor complex to be equivalent to a receptor tyrosine kinase

The Janus kinases are considered to be cytoplasmic kinases that constitutively associate with the cytoplasmic region of cytokine receptors, and the Janus kinases (Jaks) are crucial for cytokine signal transduction. We investigated Jak1 localization using subcellular fractionation techniques and fluorescence microscopy (immunofluorescence and yellow fluorescent protein-tagged Jaks). In the different experimental approaches we found Jak1 (as well as Jak2 and Tyk2) predominantly located at membranes. In contrast to previous reports we did not observe Jak proteins in significant amounts within the nucleus or in the cytoplasm. The cytoplasmic localization observed for the Jak1 mutant L80A/Y81A, which is unable to associate with cytokine receptors, indicates that Jak1 does not have a strong intrinsic membrane binding potential and that only receptor binding is crucial for the membrane recruitment. Finally we show that Jak1 remains a membrane-localized protein after cytokine stimulation. These data strongly support the hypothesis that cytokine receptor.Janus kinase complexes can be regarded as receptor tyrosine kinases.     

Cytokine receptors and signal transduction.

Most of the recently cloned cytokine receptors that operate in the immune and hematopoietic systems contain no tyrosine kinase domains in their cytoplasmic regions, unlike the family of growth factor receptors defined earlier. However, they can be assigned to several new types of receptor families based on structural similarities among them. It is characteristic of these receptors that many of them require a receptor-associated molecule in order to achieve high-affinity ligand binding and/or transmission of cytoplasmic signals. Receptor-associated molecules have been found that transduce cytoplasmic signals and are shared by different cytokine receptors. Phosphorylation of the receptors and of various cytoplasmic proteins after ligand stimulation seems to be a common event in cytokine systems. Insight into the pleiotropic and redundant nature of cytokine action is provided by the discovery of several new cytokine receptor families and of shared signal transduction molecules and by the idea that several cytoplasmic kinases may be able to functionally substitute for one another in transmitting cytokine signals.     

EGF receptor crosstalks with cytokine receptors leading to the activation of c-Jun kinase in response to UV irradiation in human keratinocytes

Ultraviolet (UV) irradiation causes photoageing through induction of matrix-degrading metalloproteinases (MMP), which are upregulated by activator protein-1 (AP-1) (Jun/Fos). The c-Jun kinase activity proves to be critically important in the regulation of AP-1 activity. Our previous studies showed that UV irradiation activates epidermal growth factor receptor (EGFR) and cytokine receptors leading to the activation of c-Jun kinase in cultured human skin keratinocytes in vitro and in human skin in vivo. However, the mechanism of UV-induced cell surface receptor activation and the crosstalk among growth factor receptor and cytokine receptors were not fully investigated. This study showed that UV (30 mJ/cm(2))-induced EGFR tyrosine phosphorylation in a manner similar to EGF (100 ng/ml), or IL-1beta (10 ng/ml) in cultured human keratinocytes. In all cases, EGFR tyrosine phosphorylation was completely inhibited by pretreatment of PD153035 (100 nM, 1 h). Also observed was that UV induced autophosphorylation of interleukin 1 receptor associated kinase (IRAK) in a manner analogous to IL-1beta or EGF. In both UV and EGF cases, the phosphorylation of IRAK was inhibited by pretreatment of PD153035. However, IL-1beta-induced IRAK activation was not affected by PD153035. In vitro kinase assay using GST-c-Jun as a substrate revealed that pretreatment of PD153035 completely inhibited UV- and IL-1-induced c-Jun kinase activity in cultured keratinocytes. Taken together, the above data suggest that EGFR plays dominant role in the crosstalk among growth factor receptor and cytokine receptors leading to the activation of c-Jun kinase upon UV irradiation, and that EGFR could be one of the targets for clinical and cosmetical prevention of UV-induced skin aging.     

Oncostatin M: signal transduction and biological activity

Oncostatin M (OSM) is a multifunctional cytokine produced by activated T lymphocytes and monocytes that is structurally and functionally related to the subfamily of cytokines known as the IL-6-type cytokine family. OSM shares properties with all members of this family of cytokines, but is most closely related structurally and functionally to LIE OSM acts on a wide variety of cells and elicits diversified biological responses in vivo and in vitro which suggest potential roles in the regulation of gene activation, cell survival, proliferation and differentiation. OSM and LIF can bind to the same functional receptor complex (LIF-receptor beta and gp130 heteromultidimers) and thus mediate overlapping spectra of biological activities. There is a second specific beta receptor that binds OSM with high affinity and also involves the subunit gp130. The two receptors for OSM can be functionally different and be coupled to different signal transduction pathways. OSM-specific receptors are expressed in a wide variety of cell types and do not possess an intrinsic tyrosine kinase domain, but the JAK/STAT tyrosine kinase pathway mediates signal transduction.     

Involvement of the ubiquitin-proteasome pathway in the degradation of nontyrosine kinase-type cytokine receptors of IL-9, IL-2, and erythropoietin

The ubiquitin-dependent proteasome-mediated (Ub-Pr) degradation pathway has been shown to regulate a large variety of substrates, including nuclear, cytosolic, and membrane proteins. In mammalian systems, polyubiquitin modification has been identified in a number of cell surface receptors for more than a decade; however, its biological significance has remained unclear until recently. For growth factor receptors with intrinsic tyrosine kinase domains, polyubiquitination is believed to trigger the internalization and subsequent degradation via the lysosomal pathway. In this study we provide the first evidence that non-tyrosine kinase-type cytokine surface receptors, IL-9R alpha-chain, IL-2 receptor ss-chain, and erythropoietin receptor, can be polyubiquitinated and degraded by proteasomes. The Ub-Pr pathway regulates both the basal level turnover and the ligand-induced degradation of the receptors. A previously identified putative molecular chaperon, valosin-containing protein, undergoes tyrosine phosphorylation in a cytokine-dependent manner and associates with the receptor complexes following receptor engagement, suggesting that valosin-containing protein may target the ubiquitinated receptors to the proteasome for degradation.     

Janus kinase 2 determinants for growth hormone receptor association,surface assembly,and signaling

GH signaling depends on functional interaction of the GH receptor (GHR) and the cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2), which possesses a C-terminal kinase domain, a catalytically inactive pseudokinase domain just N-terminal to the kinase domain, and an N-terminal half shown by us and others to harbor elements for GHR association. Computational analyses indicate that JAKs contain in their N termini ( approximately 450 residues) divergent FERM domains. FERM domains (or subdomains within them) in JAKS may be important for associations with cytokine receptors. For some cytokine receptors, JAK interaction may be required for receptor surface expression. We previously demonstrated that a JAK2 mutant devoid of its N-terminal 239 residues (JAK2-Delta1-239) did not associate with GHR and could not mediate GH- induced signaling. In this report we employ a JAK2-deficient cell line to further define N-terminal JAK2 regions required for physical and functional association with the GHR. We also examine whether JAK2 expression affects cell surface expression of the GHR. Our results suggest that FERM motifs play an important role in the interaction of GHR and JAK2. While JAK2 expression is not required for detectable surface GHR expression, an increased JAK2 level increases the fraction of GHRs that achieves resistance to deglycosylation by endoglycosidase H, suggesting that the GHR-JAK2 association may enhance either the receptor's efficiency of maturation or its stability. Further, we report evidence for the existence of a novel GH-inducible functional interaction between JAK2 molecules that may be important in the mechanism of GH-triggered JAK2 signaling.     

JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region.

The high-affinity receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) consists of a unique alpha chain and a beta c subunit that is shared with the receptors for interleukin-3 (IL-3) and IL-5. Two regions of the beta c chain have been defined; these include a membrane-proximal region of the cytoplasmic domain that is required for mitogenesis and a membrane-distal region that is required for activation of Ras, Raf-1, mitogen-activated protein kinase, and S6 kinase. Recent studies have implicated the cytoplasmic protein tyrosine kinase JAK2 in signalling through a number of the cytokine receptors, including the IL-3 and erythropoietin receptors. In the studies described here, we demonstrate that GM-CSF stimulation of cells induces the tyrosine phosphorylation of JAK2 and activates its in vitro kinase activity. Mutational analysis of the beta c chain demonstrates that only the membrane-proximal 62 amino acids of the cytosolic domain are required for JAK2 activation. Thus, JAK2 activation is correlated with induction of mitogenesis but does not, alone, activate the Ras pathway. Carboxyl truncations of the alpha chain, which inactivate the receptor for mitogenesis, are unable to mediate GM-CSF-induced JAK2 activation. Using baculovirus-expressed proteins, we further demonstrate that JAK2 physically associates with the beta c chain but not with the alpha chain. Together, the results further support the hypothesis that the JAK family of kinase are critical to coupling cytokine binding to tyrosine phosphorylation and ultimately mitogenesis.