SOCS3在乳腺癌中的研究进展

细胞因子信号抑制因子(suppressor of cytokine signaling,SOCS)是一类对细胞因子、生长因子等信号作出应答的蛋白。这类蛋白能够通过负反馈调节JAK/STAT信号通路来减弱细胞因子信号的转导。SOCS3即为一个十分有代表性的SOCS家族蛋白。大量研究表明,风湿性关节炎、糖尿病及肿瘤等疾病的发生往往同SOCS3的异常表达有着密切联系。在乳腺癌中,SOCS3能够调控肿瘤细胞的干性、转移、侵袭、耐药性等。因此,SOCS3表达的正常与否同乳腺癌病人的愈后状况在很大程度上也具有相关性。基于SOCS3同乳腺癌发生发展间的联系,本综述将对SOCS3的基本结构、分子功能及近年来该蛋白在乳腺癌中的相关研究进行简要总结。     

SOCS家族蛋白在病毒感染中发挥的作用

SOCS(Suppressor of cytokine signaling),是一种细胞因子信号通路抑制蛋白,目前认为该蛋白家族可以调节LIF(Leukemia inhibitory factor)、G-CSF(Granulocyte colony-stimulating factor)、IL-6(Interleukin-6)、IL-10(Interleukin-10)、IFN-λ(interferon-λ)等30多种细胞因子,而这些因子是机体抵抗入侵的外来病原体的主要免疫防御反应。病毒在感染宿主的过程中通过劫持宿主中的SOCS蛋白,从而对细胞中的JAK/STAT、NF-κB等与抗病毒因子调控相关的信号通路以及对T细胞的分化的调控调节病毒感染。近年来,大量的文献证实SOCS蛋白的变化与病毒感染的程度以及愈后的器官损伤具有紧密的联系,使得SOCS蛋白作为抗病毒靶点的研究尤为重要。本文主要讨论SOCS蛋白通过调控JAK-STAT、NF-κB等信号通路,在病毒感染过程中发挥的作用和作用机制。     

细胞因子发信号阻抑蛋白SOCS3作用机制及其在相关疾病中的研究

SOCS家族是JAK／STAT通路的反馈抑制因子,又被称为细胞的“分子刹车”。SOCS3是该家族中目前研究最热,也是最为清楚的成员之一。该系统介绍了近几年对SOCS3结构、功能以及临床上的最新研究进展．并分析了今后可能的研究方向。     

SOCS3在病理性疼痛中的作用

细胞因子信号传导抑制因子3(SOCS3)是细胞因子信号传导抑制因子蛋白质家族(SOCS)的一员。SOCS3是一种重要的细胞内蛋白质,在体内负调控细胞因子介导的信号通路,参与机体免疫、生长、造血、新陈代谢及肿瘤增殖等各种关键过程。近年的研究发现,SOCS3参与疼痛的调控,在神经病理性疼痛、炎性疼痛等多种类型疼痛及吗啡耐受中发生表达的变化。在坐骨神经慢性压迫损伤(CCI)模型中,磷酸二聚化的STAT3转移到细胞核内诱导脊髓背角SOCS3表达增加,在完全弗氏佐剂(CFA)炎性疼痛大鼠中,下丘脑室旁核(PVN)内SOCS3在急性期蛋白质表达水平增加、其慢性期表达下降,在骨癌疼痛大鼠腰2～5背根神经节(DRG)中SOCS3蛋白质水平显著下降。鞘内注射SOCS3慢病毒载体、阿司匹林触发的脂蛋白A4(ATL)和芍药苷,或通过抑制非编码RNA表达降低非编码RNA对SOCS3的抑制作用,能够增加SOCS3表达发挥镇痛作用。SOCS3通过抑制Janus激酶/信号转导子和转录激活子3(JAK/STAT3)信号通路及下游基因的表达,阻碍白细胞介素-1(IL-1)、IL-6和肿瘤坏死因子α(TNF-α)等多种炎...     

SOCS家族在中枢神经系统的研究进展

细胞因子信号抑制因子（SOCS）家族是一类对细胞因子信号通路具有负反馈调节作用的蛋白分子,参与多种细胞因子、生长因子和激素的信号调节。细胞因子对中枢神经系统中的各种生物效应具有广泛多样的调节作用,SOCS家族的许多成员在发育时期和成年的脑内均有表达,SOCS家族不仅与细胞因子信号调节及中枢神经系统多种功能的调节密切相关,而且可能是神经发育和分化的重要调控因子,并参与神经免疫内分泌调节。本文综述了SOCS家族的发现、结构特点、脑内分布以及在中枢神经系统中的功能等方面的研究进展。     

SOCS超甲基化与肿瘤发生

细胞因子信号转导抑制分子(suppressor of cytokine signaling,SOCS)是一类在细胞信号转导过程中发挥重要作用的负调控因子,可抑制多种细胞因子的信号转导,从而实现对体内多种免疫反应的调控作用.近年来研究发现,SOCS启动子区域内CpG岛的超甲基化导致的基因转录沉默与多种肿瘤的发生密切相关.SOCS蛋白作为信号转导途径的负调节物,代表着一类肿瘤抑制基因,成为治疗肿瘤的新靶标.     

信号传导的负性调节因子家族SOCS

细胞因子和相应受体结合,引发细胞内信号分子级联反应,而SOCS蛋白负性调节细胞因子的JAK-STATs信号传导途径,且SOCS蛋白作用的直接靶点不同。另一方面STATs可以和SOCS基因的调控序列结合,调节SOCS基因的表达,小鼠SOCS基因敲除实验显示,该信号负反馈途径有助于调节细胞适度应答,结构上,SOCS中间为SH2结构域。C-末端是保守的SOCS盒,因N-末端差异较大而将SOCS家族分为5组。     

SOCS1在氯胺酮减轻小胶质细胞活化中的机制研究

目的:探讨麻醉药氯胺酮(Ketamine, KET)对暴露于脂多糖(Lipopolysaccharide, LPS)中的小胶质细胞活化水平的影响,并观察细胞因子信号转导抑制因子1(Suppressor of Cytokine Signaling 1, SOCS1)在其中的作用。方法:本研究选用N9小胶质细胞系,将其暴露于浓度为10 ng/mL的LPS中,模拟炎症反应,同时给与浓度为1 m M的KET,采用Western blot、酶联免疫吸附检测(Enzyme-Linked Immunosorbent Assay, ELISA)小RNA干扰和免疫细胞染色等方法,观察KET对暴露于LPS中的小胶质细胞活化水平的影响,及SOCS1分子在其中的作用。结果:将细胞分为3组,分别为正常培养的Control组、LPS组和KET+LPS组,研究发现,将N9小胶质细胞暴露于含10 ng/mL的细胞培养基中24 h后,细胞诱导型一氧化氮合酶(Inducible Nitric Oxide Synthase, i NOS)表达和培养基肿瘤坏死因子α(Tumor Necrosis Factorα, TNF-α)含量显著增加(P0.05),而KET可显著降i NOS蛋白表达和培养基TNF-α含量(P0.05)。随后,将细胞分为5组,分别为Control组、LPS组、KET+LPS组、SOCS1-siRNA+KET+LPS组和乱序siRNA(SC-siRNA)+KET+LPS组,我们发现,LPS可显著增加小胶质细胞TNF-α和白细胞介素1β(Interleukin-1β, IL-1β)的释放、增加SOCS1和核因子κB(Neuclear FactorκB, NF-κB)表达(P0.05),而KET可显著逆转LPS对炎症因子释放和NF-κB表达的影响,并进一步增加SOCS1表达(P0.05),而SOCS1-siRNA显著逆转了KET的上述作用(P0.05),SC-siRNA未对KET产生的上述作用造成显著影响(P0.05)。结论:KET可降低LPS对小胶质细胞的活化作用,上述作用可能通过SOCS1分子介导。     

Functional cross-modulation between SOCS proteins can stimulate cytokine signaling

SOCS (suppressors of cytokine signaling) proteins are negative regulators of cytokine signaling that function primarily at the receptor level. Remarkably, in vitro and in vivo observations revealed both inhibitory and stimulatory effects of SOCS2 on growth hormone signaling, suggesting an additional regulatory level. In this study, we examined the possibility of direct cross-modulation between SOCS proteins and found that SOCS2 could interfere with the inhibitory actions of other SOCS proteins in growth hormone, interferon, and leptin signaling. This SOCS2 effect was SOCS box-dependent, required recruitment of the elongin BC complex, and coincided with degradation of target SOCS proteins. Detailed mammalian protein-protein interaction trap (MAPPIT) analysis indicated that SOCS2 can interact with all members of the SOCS family. SOCS2 may thus function as a molecular bridge between a ubiquitin-protein isopeptide ligase complex and SOCS proteins, targeting them for proteasomal turnover. We furthermore extended these observations to SOCS6 and SOCS7. Our findings point to a unique regulatory role for SOCS2, SOCS6, and SOCS7 within the SOCS family and provide an explanation for the unexpected phenotypes observed in SOCS2 and SOCS6 transgenic mice.     

Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling

Suppressor of cytokine signaling (SOCS) proteins are a family of Src homology 2-containing adaptor proteins. Cytokine-inducible Src homology domain 2-containing protein, SOCS1, SOCS2, and SOCS3 have been implicated in the down-regulation of cytokine signaling. The function of SOCS4, 5, 6, and 7 are not known. KIT receptor signaling is regulated by protein tyrosine phosphatases and adaptor proteins. We previously reported that SOCS1 inhibited cell proliferation in response to stem cell factor (SCF). By screening the other members of SOCS family, we identified SOCS6 as a KIT-binding protein. Using KIT mutants and peptides, we demonstrated that SOCS6 bound directly to KIT tyrosine 567 in the juxtamembrane domain. To investigate the function of this interaction, we constitutively expressed SOCS6 in cell lines. Ectopic expression of SOCS6 in Ba/F3-KIT cell line decreased cell proliferation in response to SCF but not SCF-induced chemotaxis. SOCS6 reduced SCF-induced activation of ERK1/2 and p38 but not activation of AKT or STATs in Ba/F3, murine embryonic fibroblast (MEF), or COS-7 cells. SOCS6 did not impair ERK and p38 activation by other stimuli. These results indicate that SOCS6 binds to KIT juxtamembrane region, which affects upstream signaling components leading to MAPK activation. Our results indicate that KIT signaling is regulated by several SOCS proteins and suggest a putative function for SOCS6 as a negative regulator of receptor tyrosine kinases.     

Tyrosine-phosphorylated SOCS3 interacts with the Nck and Crk-L adapter proteins and regulates Nck activation

Suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine and growth factor signal transduction. Although the affect of SOCS proteins on the Jak-STAT pathway has been well characterized, their role in the regulation of other signaling modules is not well understood. In the present study, we demonstrate that SOCS3 physically interacts with the SH2/SH3-containing adapter proteins Nck and Crk-L, which are known to couple activated receptors to multiple downstream signaling pathways and the actin cytoskeleton. Our data show that the SOCS3/Nck and SOCS3/Crk-L interactions depend on tyrosine phosphorylation of SOCS3 Tyr(221) within the conserved SOCS box motif and intact SH2 domains of Nck and Crk-L. Furthermore, SOCS3 Tyr(221) forms a YXXP motif, which is a consensus binding site for the Nck and Crk-L SH2 domains. Expression of SOCS3 in NIH3T3 cells induces constitutive recruitment of a Nck-GFP fusion protein to the plasma membrane and constitutive tyrosine phosphorylation of endogenous Nck. Our findings suggest that SOCS3 regulates multiple cytokine and growth factor-activated signaling pathways by acting as a recruitment factor for adapter proteins.     

Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling

Suppressors of cytokine signaling (SOCS) are Src homology-2-containing proteins originally identified as negative regulators of cytokine signaling. Accumulating evidence indicates a role for SOCS proteins in the regulation of additional signaling pathways including receptor tyrosine kinases. Notably, SOCS36E, the Drosophila ortholog of mammalian SOCS5, was recently implicated as a negative regulator of the Drosophila ortholog of EGFR. In this study, we aimed at characterizing the role of SOCS5 in the negative regulation of EGFR. Here we show that the expression of SOCS5 and its closest homolog SOCS4 is elevated in cells following treatment with EGF, similar to several negative feedback regulators of EGFR whose expression is up-regulated upon receptor activation. The expression of SOCS5 led to a marked reduction in EGFR expression levels by promoting EGFR degradation. The reduction in EGFR levels and EGF-induced signaling in SOCS5-expressing cells requires both the Src homology-2 and SOCS box domains of SOCS5. Interestingly, EGFR is degraded by SOCS5 prior to EGF treatment in a ligand- and c-Cbl-independent manner. SOCS5 can associate with EGFR and can also bind the ElonginBC protein complex via its SOCS box, which may recruit an E3 ubiquitin ligase to promote EGFR degradation. Thus, we have characterized a novel function for SOCS5 in regulating EGFR and discuss its potential role in controlling EGFR homeostasis.     

Oncostatin M receptor-mediated signal transduction is negatively regulated by SOCS3 through a receptor tyrosine-independent mechanism

Down-regulation of interleukin (IL)-6-type cytokine signaling has been shown to occur, among other mechanisms, via induction of the feedback inhibitor SOCS3 (suppressor of cytokine signaling 3). Binding of SOCS3 to the phosphorylated Tyr(759) in the cytoplasmic region of gp130, the common signal transducing receptor chain of all IL-6-type cytokines, is necessary for inhibition of Janus kinase-mediated signaling. In the present study, we analyzed the effect of SOCS3 on signal transduction by the proinflammatory cytokine oncostatin M (OSM), which signals through a receptor complex of gp130 and the OSM receptor (OSMR). OSM leads to a much stronger and prolonged induction of SOCS3 in HepG2 hepatoma cells and murine embryonal fibroblasts (MEF) compared with IL-6. A negative effect of SOCS3 on OSM signaling was confirmed using MEF cells lacking SOCS3. We can show that the OSMR-mediated signaling is inhibited by SOCS3 to a similar extent as previously described for gp130. However, the inhibition occurs independent of tyrosine motifs within the OSMR. Instead, SOCS3 interacts directly with JAK1 in a stimulation-dependent manner, a mechanism so far only known for SOCS1.     

NOTCH1 up-regulation and signaling involved in Mycobacterium bovis BCG-induced SOCS3 expression in macrophages

Suppressor of cytokine signaling (SOCS) 3 is a critical negative regulator of cytokine signaling and is induced by Mycobacterium bovis Bacille Calmette-Guérin (M. bovis BCG) in mouse macrophages. However, little is known about the early receptor proximal signaling mechanisms underlying mycobacteria-mediated induction of SOCS3. We demonstrate here for the first time that M. bovis BCG up-regulates NOTCH1 and activates the NOTCH1 signaling pathway, leading to the expression of SOCS3. We show that perturbing Notch signaling in infected macrophages results in the marked reduction in the expression of SOCS3. Furthermore, enforced expression of the Notch1 intracellular domain in RAW 264.7 macrophages induces the expression of SOCS3, which can be further potentiated by M. bovis BCG. The perturbation of Toll-like receptor (TLR) 2 signaling resulted in marked reduction in SOCS3 levels and expression of the NOTCH1 target gene, Hes1. The down-regulation of MyD88 resulted in a significant decrease in SOCS3 expression, implicating the role of the TLR2-MyD88 axis in M. bovis BCG-triggered signaling. However, the SOCS3 inducing ability of M. bovis BCG remains unaltered also upon infection of macrophages from TLR4-defective C3H/HeJ mice. More importantly, signaling perturbation data suggest the involvement of cross-talk among members of the phosphoinositide 3-kinase and mitogen-activated protein kinase cascades with NOTCH1 signaling in SOCS3 expression. Furthermore, SOCS3 expression requires the NOTCH1-mediated recruitment of Suppressor of Hairless (CSL) and nuclear factor-kappaB to the Socs3 promoter. Overall, these results implicate NOTCH1 signaling during inducible expression of SOCS3 following infection of macrophages with an intracellular bacillus-like M. bovis BCG.     

Suppressor of cytokine signaling 1 inhibits IL-10-mediated immune responses

IL-10 has proved to be a key cytokine in regulating inflammatory responses by controlling the production and function of various other cytokines. The suppressor of cytokine signaling (SOCS) gene products are a family of cytoplasmic molecules that are essential mediators for negatively regulating cytokine signaling. It has been previously shown that IL-10 induced SOCS3 expression and that forced constitutive expression of SOCS3 inhibits IL-10/STAT3 activation and LPS-induced macrophage activation. In this report, we show that, in addition to SOCS3 expression, IL-10 induces SOCS1 up-regulation in all cell lines tested, including Ba/F3 pro-B cells, MC/9 mast cells, M1 leukemia cells, U3A human fibroblasts, and primary mouse CD4(+) T cells. Induction of SOCS molecules is dependent on STAT3 activation by IL-10R1. Cell lines constitutively overexpressing SOCS proteins demonstrated that SOCS1 and SOCS3, but not SOCS2, are able to partially inhibit IL-10-mediated STAT3 activation and proliferative responses. Pretreatment of M1 cells with IFN-gamma resulted in SOCS1 induction and a reduction of IL-10-mediated STAT3 activation and cell growth inhibition. IL-10-induced SOCS is associated with the inhibition of IFN-gamma signaling in various cell types, and this inhibition is independent of C-terminal serine residues of the IL-10R, previously shown to be required for other anti-inflammatory responses. Thus, the present results show that both SOCS1 and SOCS3 are induced by IL-10 and may be important inhibitors of both IL-10 and IFN-gamma signaling. IL-10-induced SOCS1 may directly inhibit IL-10 IFN-gamma signaling, while inhibition of other proinflammatory cytokine responses may use additional IL-10R1-mediated mechanisms.     

Suppressor of Cytokine Signaling (SOCS) 5 Utilises Distinct Domains for Regulation of JAK1 and Interaction with the Adaptor Protein Shc-1

Suppressor of Cytokine Signaling (SOCS)5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF) signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR). Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling.