细胞常见信号通路图片合集

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细胞信号转导通路

Chromatin/Epigenetics Resources
Overview of Chromatin / Epigenetics
Chromatin regulation refers to the events affecting chromatin structure and therefore, transcriptional control of gene expression patterns. Epigenetics, specifically, refers to the heritable modifications which result in altered gene expression and are not known to be encoded in DNA. The nucleosome, made up of four histone proteins (H2A, H2B, H3, and H4), is the primary building block of chromatin. Originally thought to function as a static scaffold for DNA packaging, histones have more recently been shown to be dynamic proteins, undergoing multiple types of post-translational modifications (PTMs) and interacting with regulatory proteins to control gene expression. Protein acetylation plays a crucial role in regulating chromatin structure and transcriptional activity. Histone hyperacetylation by histone acetyltransferases (HATs) is associated with transcriptional activation, whereas histone deacetylation by histone deacetylases (HDACs) is associated with transcriptional repression. Hyperacetylation can directly affect chromatin structure by neutralizing the positive charge on histone tails and disrupting nucleosome-nucleosome and nucleosomeDNA interactions. In addition, acetylation creates binding sites for bromodomain-containing chromatin regulatory proteins (histone modification readers). Unlike acetylation, methylation does not alter the charge of arginine and lysine residues and is unlikely to directly modulate nucleosomal interactions required for chromatin folding. Methylated arginine and lysine residues are major determinants for formation of active and inactive regions of the genome. Methylation facilitates binding of chromatin regulatory proteins/histone modification readers that contain various methyl-lysine or methyl-arginine binding domains (PHD, chromo, WD40, Tudor, MBT, Ankyrin repeats, PWWP domains). Recruitment of co-activator and co-repressor proteins is dependent on the specific lysine residue that is modified. The modulation of chromatin structure is an essential component in the regulation of transcriptional activation and repression. One strategy by which chromatin structure can be modulated is through disruption of histone-DNA contacts by ATP-dependent chromatin remodelers, such as the NuRD, Polycomb, and SWI/SNF complexes, which have been shown to regulate gene activation/repression, cell growth, the cell cycle, and differentiation. Chromatin structure is also modulated through other PTMs such as phosphorylation of histone proteins, which affects association with DNA-interacting proteins and has been recently identified to play a role in coordinating other histone modifications. Furthermore, methylation of DNA at cytosine residues in mammalian cells affects chromatin folding and is a heritable, epigenetic modification that is critical for proper regulation of gene silencing, genomic imprinting, and development. Three families of mammalian DNA methyl-transferases have been identified, DNMT1/2/3, that play distinct roles in embryonic stem cells and adult somatic cells. In addition to the core histone proteins, a number of histone variants exist that confer different structural properties to nucleosomes and play a number of specific functions such as DNA repair, proper kinetochore assembly and chromosome segregation during mitosis, and regulation of transcription. Chromatin and epigenetic regulation is crucial for proper programming of the genome during development and under stress conditions, as the misregulation of gene expression can lead to diseased states such as cancer.

常见信号通路

常见信号通路.常见的⼏种信号通路信号通路1 JAK-STAT 蛋⽩与STAT1) JAK信号通路是近年来发现的⼀条由细胞因⼦刺激的信号转导通路，参与细胞的增JAK-STAT与其它信号通路相⽐，这条信号通凋亡以及免疫调节等许多重要的⽣物学过程。

殖、分化、JAK 酪氨酸激酶它主要由三个成分组成，即酪氨酸激酶相关受体、路的传递过程相对简单，。

和转录因⼦STAT ）酪氨酸激酶相关受体（tyrosine kinase associated receptor(1)、IL-2?7）这包括⽩介素JAK-STAT信号通路来传导信号，2?7（许多细胞因⼦和⽣长因⼦通过（表⽪⽣长因⼦）、（⽣长激素）、EGF（粒细胞/巨噬细胞集落刺激因⼦）、GHGM-CSF（⼲扰素）等等。

这些细胞因⼦和⽣长因⼦在细胞膜上（⾎⼩板衍⽣因⼦）以及IFNPDGF但胞内段具有酪氨酸激酶有相应的受体。

这些受体的共同特点是受体本⾝不具有激酶活性，的活化，来磷酸化各种靶蛋的结合位点。

受体与配体结合后，通过与之相结合的JAKJAK ⽩的酪氨酸残基以实现信号从胞外到胞内的转递。

Janus kinase）酪氨酸激酶JAK（(2)receptor很多酪氨酸激酶都是细胞膜受体，它们统称为酪氨酸激酶受体（Janus kinase是英⽂JAK却是⼀类⾮跨膜型的酪氨酸激酶。

JAKtyrosine kinase, RTK），⽽在罗马神话中是掌管开始和终结的两⾯神。

之所以称为两⾯神激酶，是因为Janus的缩写，结构域的信号分SH2JAK既能磷酸化与其相结合的细胞因⼦受体，⼜能磷酸化多个含特定个，它们在结构上有Tyk27JAK2、JAK3以及个成员：⼦。

JAK蛋⽩家族共包括4JAK1、结构域结构域为激酶区、JH2同源结构域（JAK homology domain, JH），其中JH1JAK JH7是受体结合区域。

是“假”激酶区、JH6和“信被称为）STAT(3) 转录因⼦STAT（signal transducer and activator of transcription在信号转导和转录激活上发挥了关键性的作⽤。

《细胞凋亡信号通路》课件

细胞增殖与细胞凋亡的平衡
研究细胞凋亡与细胞增殖之间的平衡关系，理解其在组织发育和肿瘤形成中的作用。
细胞凋亡与自噬的相互作用
探索细胞凋亡与自噬之间的相互影响，揭示其在维持细胞稳态和疾病发展中的作用。
细胞凋亡与细胞信号转导通路的关系
解析细胞凋亡与其他信号转导通路之间的联系和相互作用，为药物研发提供新的靶点。
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肿瘤细胞通过抑制细胞凋亡信号通路，逃逸机体免疫监视，实现恶性增殖。
细胞凋亡信号通路的异常与肿瘤的发生、发展密切相关，为肿瘤的诊断和治疗提供了新的思路。
针对肿瘤细胞中细胞凋亡信号通路的异常，开发新型抗肿瘤药物和治疗策略，具有重要的临床意义。
神经退行性疾病如阿尔茨海默病、帕金森病等，其发病机制与细胞凋亡信号通路的异常密切相关。
神经元细胞的凋亡是神经退行性疾病发生发展的重要病理过程，对神经元细胞的保护和凋亡的抑制是治疗神经退行性疾病的重要方向。
研究细胞凋亡信号通路在神经退行性疾病中的作用，有助于深入理解疾病的发病机制，为治疗提供新的思路和方法。
心肌细胞的凋亡可以导致心肌功能减退、心室重构等病理改变，进一步加重心血管疾病的发展。
细胞凋亡的调控机制
CATALOGUE
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基因突变与细胞凋亡
基因突变可以影响细胞凋亡的敏感性，一些基因的突变可以促进或抑制凋亡过程。
基因组稳定性与细胞凋亡
基因组的稳定性对于细胞的生存和凋亡具有重要意义，某些基因与维持基因组稳定性相关，从而影响细胞凋亡。
基因表达调控
基因表达的改变是细胞凋亡的重要调控方式之一，某些基因在凋亡过程中被激活或抑制，从而影响细胞命运。
线粒体通路概述：线粒体通路是一种由线粒体释放的凋亡相关分子介导的凋亡信号转导通路。当细胞受到某些刺激时，线粒体会释放出凋亡相关分子，如细胞色素C和Smac等，这些分子会进一步激活下游的caspase级联反应，导致细胞凋亡。

信号通路合辑

信号通路合辑纵观现如今的科研发展趋势，⽆论哪⽅⾯的研究都脱离不了分⼦机制，其实归根结底就是搞明⽩信号通路中上下游的基因是如何调控的，受到了哪些因素的影响。

华美⽣物特别整理了各研究领域信号通路⽰意图，以便于我们获取最直接的科研思路。

AMPK signaling pathway腺苷酸激活蛋⽩激酶 (AMPK) 在细胞能量稳态调节中起到关键作⽤。

在低⾎糖、低氧、缺⾎和热休克等情况下，可激活AMPK。

AMPK可作为异源三聚体复合体出现，内含⼀个催化性α亚单位和调节性β和γ亚单位。

AMP结合到γ亚单位后，可变构激活复合体，使其苏氨酸172位点更易磷酸化的底物，在α亚单位的激活环中更易被主要的上游AMPK激酶LKB1 磷酸化。

AMPK还能被CAMKK2在苏氨酸172位点直接磷酸化，这是由代谢激素（如脂联素和瘦素）刺激后胞内钙离⼦⽔平变化引起的反应。

作为细胞能量感受器，AMPK 可对ATP低⽔平做出反应，被激活后，可对补充细胞 ATP 供应的信号转导通路做出正向调控，这些通路包括脂肪酸氧化和⾃噬。

Apoptosis细胞凋亡，为⼀种细胞程序性死亡。

相对于细胞坏死（necrosis），细胞凋亡是细胞主动实施的。

细胞凋亡⼀般由⽣理或病理性因素引起。

⽽细胞坏死则主要为缺氧造成，两者可以很容易通过观察区分开来。

Caspase家族属于半胱氨酸蛋⽩酶。

起始组Caspase包括caspase-2,-8,-9,-10,-11和-12,与促凋亡信号紧密相连，⼀旦激活，这些酶会切割并激活下游的效应组Caspase，包括Caspase-3,-6,-7。

效应 Caspase通过对细胞内蛋⽩特定的天冬氨酸残基位置处进⾏切割实现细胞的凋亡。

FasL和 TNF对Fas和 TNFR的结合能够激活caspase-8和-10。

DNA损伤诱导PIDD的表达，PIDD与RAIDD 和caspase-2结合并激活caspase-2。

受损线粒体中释放的细胞⾊素C与caspase-9的活化相关。

细胞常见信号通路图片合集

目录actin肌丝 (5)Wnt/LRP6 信号 (7)WNT信号转导 (7)West Nile 西尼罗河病毒 (8)Vitamin C 维生素C在大脑中的作用 (10)视觉信号转导 (11)VEGF，低氧 (13)TSP-1诱导细胞凋亡 (15)Trka信号转导 (16)dbpb调节mRNA (17)CARM1甲基化 (19)CREB转录因子 (20)TPO信号通路 (21)Toll-Like 受体 (22)TNFR2 信号通路 (24)TNFR1信号通路 (25)IGF-1受体 (26)TNF/Stress相关信号 (27)共刺激信号 (29)Th1/Th2 细胞分化 (30)TGF beta 信号转导 (32)端粒、端粒酶与衰老 (33)TACI和BCMA调节B细胞免疫 (35)T辅助细胞的表面受体 (36)T细胞受体信号通路 (37)T细胞受体和CD3复合物 (38)Cardiolipin的合成 (40)Synaptic突触连接中的蛋白 (42)HSP在应激中的调节的作用 (43)Stat3 信号通路 (45)SREBP控制脂质合成 (46)酪氨酸激酶的调节 (48)Sonic Hedgehog (SHH)受体ptc1调节细胞周期 (51)Sonic Hedgehog (Shh) 信号 (53)SODD/TNFR1信号 (56)AKT/mTOR在骨骼肌肥大中的作用 (58)G蛋白信号转导 (59)IL1受体信号转导 (60)acetyl从线粒体到胞浆过程 (62)趋化因子chemokine在T细胞极化中的选择性表达 (63)SARS冠状病毒蛋白酶 (65)SARS冠状病毒蛋白酶 (67)Parkin在泛素-蛋白酶体中的作用 (69)nicotinic acetylcholine受体在凋亡中的作用 (71)线粒体在细胞凋亡中的作用 (73)MEF2D在T细胞凋亡中的作用 (74)Erk5和神经元生存 (75)ERBB2信号转导 (77)GPCRs调节EGF受体 (78)BRCA1调节肿瘤敏感性 (79)Rho细胞运动的信号 (81)Leptin能逆转胰岛素抵抗 (82)转录因子DREAM调节疼敏感 (84)PML调节转录 (86)p27调节细胞周期 (88)MAPK信号调节 (89)细胞因子调节造血细胞分化 (91)eIF4e和p70 S6激酶调节 (92)eIF2调节 (93)谷氨酸受体调节ck1/cdk5 (94)BAD磷酸化调节 (95)plk3在细胞周期中的作用 (96)Reelin信号通路 (97)RB肿瘤抑制和DNA破坏 (98)NK细胞介导的细胞毒作用 (99)Ras信号通路 (100)Rac 1细胞运动信号 (101)PTEN依赖的细胞生长抑制和细胞凋亡 (103)蛋白激酶A（PKA）在中心粒中的作用 (104)notch信号通路 (106)蛋白酶体Proteasome复合物 (108)Prion朊病毒的信号通路 (109)早老素Presenilin在notch和wnt信号中的作用 (110)淀粉样蛋白前体信号 (112)mRNA的poly(A)形成 (113)PKC抑制myosin磷酸化 (114)磷脂酶C（PLC）信号 (115)巨噬细胞Pertussis toxin不敏感的CCR5信号通路 (116)Pelp1调节雌激素受体的活性 (117)PDGF信号通路 (118)p53信号通路 (120)p38MAPK信号通路 (121)Nrf2是氧化应激基本表达的关键基因 (122)OX40信号通路 (123)hTert转录因子的调节作用 (124)hTerc转录调节活性图 (125)AIF在细胞凋亡中的作用 (126)Omega氧化通路 (127)核受体在脂质代谢和毒性中的作用 (129)NK细胞中NO2依赖的IL-12信号通路 (131)TOR信号通路 (133)NO信号通路 (134)NF-kB信号转导通路 (135)NFAT与心肌肥厚的示意图 (137)神经营养素及其表面分子 (139)神经肽VIP和PACAP防止活化T细胞凋亡图 (141)神经生长因子信号图 (142)细胞凋亡信号通路 (144)MAPK级联通路 (144)MAPK信号通路图 (145)BCR信号通路 (146)蛋白质乙酰化示意图 (147)wnt信号通路 (148)胰岛素受体信号通路 (149)细胞周期在G2/M期的调控机理图 (151)细胞周期G1/S检查点调控机理图 (152)Jak-STAT关系总表 (153)Jak/STAT 信号 (155)TGFbeta信号 (156)NFkappaB信号 (157)p38 MAPK信号通路 (159)SAPK/JNK 信号级联通路 (160)从G蛋白偶联受体到MAPK (161)MAPK pathwayMAPK级联信号图 (162)eIF-4E和p70 S6激酶调控蛋白质翻译 (163)eif2蛋白质翻译 (164)蛋白质翻译示意图 (165)线粒体凋亡通路 (167)死亡受体信号通路 (168)凋亡抑制通路 (170)细胞凋亡综合示意图 (171)Akt/Pkb信号通路 (172)MAPK/ERK信号通路 (174)哺乳动物MAPK信号通路 (175)Pitx2多步调节基因转录 (176)IGF-1R导致BAD磷酸化的多个凋亡路径 (177)多重耐药因子 (179)mTOR信号通路 (180)Msp/Ron受体信号通路 (181)单核细胞和其表面分子 (182)线粒体的肉毒碱转移酶（CPT）系统 (183)METS影响巨噬细胞的分化 (184)Anandamide，内源性大麻醇的代谢 (186)黑色素细胞（Melanocyte）发育和信号 (187)DNA甲基化导致转录抑制的机理图 (188)蛋白质的核输入信号图 (190)PPARa调节过氧化物酶体的增殖 (192)对乙氨基酚（Acetaminophen）的活性和毒性机理 (194)mCalpain在细胞运动中的作用 (196)MAPK信号图 (198)MAPK抑制SMRT活化 (200)苹果酸和天门冬酸间的转化 (201)低密度脂蛋白（LDL）在动脉粥样硬化中的作用 (202)LIS1基因在神经细胞的发育和迁移中的作用图 (204)Pyk2与Mapk相连的信号通路 (205)galactose代谢通路 (206)Lectin诱导补体的通路 (207)Lck和Fyn在TCR活化中的作用 (208)乳酸合成图 (209)Keratinocyte分化图 (210)离子通道在心血管内皮细胞中的作用 (211)离子通道和佛波脂（Phorbal Esters）信号 (213)内源性Prothrombin激活通路 (214)Ribosome内化通路 (216)整合素（Integrin）信号通路 (217)胰岛素（Insulin）信号通路 (218)Matrix Metalloproteinases (219)组氨酸去乙酰化抑制剂抑制Huntington病 (220)Gleevec诱导细胞增殖 (222)Ras和Rho在细胞周期的G1/S转换中的作用 (224)DR3，4，5受体诱导细胞凋亡 (225)AKT调控Gsk3图 (226)IL-7信号转导 (227)IL22可溶性受体信号转导图 (229)IL-2活化T细胞图 (230)IL12和Stat4依赖的TH1细胞发育信号通路 (232)IL-10信号通路 (233)IL 6信号通路 (234)IL 5信号通路 (236)actin肌丝Mammalian cell motility requires actin polymerization in the direction of movement to change membrane shape and extend cytoplasm into lamellipodia. The polymerization of actin to drive cell movement also involves branching of actin filaments into a network oriented with the growing ends of the fibers near the cell membrane. Manipulation of this process helps bacteria like Salmonella gain entry into cells they infect. Two of the proteins involved in the formation of Y branches and in cell motility are Arp2 and Arp3, both members of a large multiprotein complex containing several other polypeptides as well. The Arp2/3 complex is localized at the Y branch junction and induces actin polymerization. Activity of this complex is regulated by multiple different cell surface receptor signaling systems, activating WASP, and Arp2/3 in turn to cause changes in cell shape and cell motility. Wasp and its cousin Wave-1 interact with the Arp2/3 complex through the p21 component of the complex. The crystal structure of the Arp2/3 complex has revealed further insights into the nature of how the complex works.Activation by Wave-1, another member of the WASP family, also induces actinalterations in response to Rac1 signals upstream. Wave-1 is held in an inactive complex in the cytosol that is activated to allow Wave-1 to associate with Arp2/3. While WASP is activated by interaction with Cdc42, Wave-1, is activated by interaction with Rac1 and Nck. Wave-1 activation by Rac1 and Nck releases Wave-1 with Hspc300 to activate actin Y branching and polymerization by Arp2/3. Different members of this gene family may produce different actin cytoskeletal architectures. The immunological defects associated with mutation of the WASP gene, the Wiskott-Aldrich syndrome for which WASP was named, indicates the importance of this system for normal cellular function.Cory GO, Ridley AJ. Cell motility: braking WAVEs. Nature. 2002 Aug15;418(6899):732-3. No abstract available.Eden, S., et al. (2002) Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418(6899), 790-3Falet H, Hoffmeister KM, Neujahr R, Hartwig JH. Normal Arp2/3 complex activation in platelets lacking WASp. Blood. 2002 Sep 15;100(6):2113-22.Kreishman-Deitrick M, Rosen MK, Kreishman-Deltrick M. Ignition of a cellular machine. Nat Cell Biol. 2002 Feb;4(2):E31-3. No abstract available.Machesky, L.M., Insall, R.H. (1998) Scar1 and the related Wiskott-Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex. Curr Biol 8(25), 1347-56Robinson, R.C. et al. (2001) Crystal structure of Arp2/3 complex. Science 294(5547), 1679-84Weeds A, Yeoh S. Structure. Action at the Y-branch. Science. 2001 Nov23;294(5547):1660-1. No abstract available.Wnt/LRP6 信号Wnt glycoproteins play a role in diverse processes during embryonic patterning in metazoa through interaction with frizzled-type seven-transmembrane-domain receptors (Frz) to stabilize b-catenin. LDL-receptor-related protein 6 (LRP6), a Wnt co-receptor, is required for this interaction. Dikkopf (dkk) proteins are both positive and negative modulators of this signalingWNT信号转导West Nile 西尼罗河病毒West Nile virus (WNV) is a member of the Flaviviridae, a plus-stranded virus family that includes St. Louis encephalitis virus, Kunjin virus, yellow fever virus, Dengue virus, and Japanese encephalitis virus. WNV was initially isolated in 1937 in the West Nile region of Uganda and has become prevalent in Africa, Asia, and Europe. WNV has rapidly spread across the United States through its insect host and causes neurological symptoms and encephalitis, which can result in paralysis or death. Since 1999 about 3700 cases of West Nile virus (WNV) infection and 200 deaths have been recorded in United States. The viral capsid protein likely contributes to theWNV-associated deadly inflammation via apoptosis induced through the mitochondrial pathway.WNV particles (50 nm in diameter) consist of a dense core (viral protein C encapsidated virus RNA genome) surrounded by a membrane envelope (viral E and M proteins embedded in a lipid bilayer). The virus binds to a specific cell surface protein (not yet identified), an interaction thought to involve E protein with highly sulfated neperan sulfate (HSHS) residues that are present on the surfaces of many cells and enters the cell by a process similar to that of endocytosis. Once inside the cell, the genome RNA is released into the cytoplasm via endosomal release, a fusion process involving acidic pH induced conformation change in the E protein. The RNA genome serves as mRNA and is translated by ribosomes into ten mature viral proteins are produced via proteolytic cleavage, which include three structural components and seven different nonstructural components of the virus. These proteins assemble and transcribe complimentary minus strand RNAs from the genomic RNA. The complimentary minus strand RNA in turns serves as template for the synthesis of positive-stranded genomic RNAs. Once viral E, preM and C proteins have accumulated to sufficient level, they assemble with the genomic RNA to form progeny virions, which migrate to the cell surface where they are surrounded with lipid envelop and released.Vitamin C 维生素C在大脑中的作用Vitamin C (ascorbic acid) was first identified by virtue of the essential role it plays in collagen modification, preventing the nutritional deficiency scurvy. Vitamin C acts as a cofactor for hydroxylase enzymes that post-translationally modify collagen to increase the strength and elasticity of tissues. Vitamin C reduces the metal ion prosthetic groups of many enzymes, maintaining activity of enzymes, also acts as an anti-oxidant. Although the prevention of scurvy through modification of collagen may be the most obvious role for vitamin C, it is not necessarily the only role of vitamin C. Svct1 and Svct2 are ascorbate transporters for vitamin C import into tissues and into cells. Both of these transporters specifically transport reduced L-ascorbic acid against a concentration gradient using the intracellular sodium gradient to drive ascorbate transport. Svct1 is expressed in epithelial cells in the intestine, upregulated in cellular models for intestinal epithelium and appears to be responsible for the import ofdietary vitamin C from the intestinal lumen. The vitamin C imported from the intestine is present in plasma at approximately 50 uM, almost exclusively in the reduced form, and is transported to tissues to play a variety of roles. Svct2 imports reduced ascorbate from the plasma into very active tissues like the brain. Deletion in mice of the gene for Svct2 revealed that ascorbate is required for normal development of the lungs and brain during pregnancy. A high concentration of vitamin C in neurons of the developing brain may help protect the developing brain from free radical damage. The oxidized form of ascorbate, dehydroascorbic acid, is transported into a variety of cells by the glucose transporter Glut-1. Glut-1, Glut-3 and Glut-4 can transport dehydroascorbate, but may not transport significant quantities of ascorbic acid in vivo.视觉信号转导The signal transduction cascade responsible for sensing light in vertebrates is one of the best studied signal transduction processes, and is initiated by rhodopsin in rodcells, a member of the G-protein coupled receptor gene family. Rhodopsin remains the only GPCR whose structure has been resolved at high resolution. Rhodopsin in the discs of rod cells contains a bound 11-cis retinal chromophore, a small molecule derived from Vitamin A that acts as the light sensitive portion of the receptor molecule, absorbing light to initiate the signal transduction cascade. When light strikes 11-cis retinal and is absorbed, it isomerizes to all-trans retinal, changing the shape of the molecule and the receptor it is bound to. This change in rhodopsin抯shape alters its interaction with transducin, the member of the G-protein gene family that is specific in its role in visual signal transduction. Activation of transducin causes its alpha subunit to dissociate from the trimer and exchange bound GDP for GTP, activating in turn a membrane-bound cyclic-GMP specific phosphodiesterase that hydrolyzes cGMP. In the resting rod cell, high levels of cGMP associate with a cyclic-GMP gated sodium channel in the plasma membrane, keeping the channels open and the membrane of the resting rod cells depolarized. This is distinct from synaptic generation of action potentials, in which stimulation induces opening of sodium channels and depolarization. When cGMP gated channels in rod cells open, both sodium and calcium ions enter the cell, hyperpolarizing the membrane and initiating the electrochemical impulse responsible for conveying the signal from the sensory neuron to the CNS. The rod cell in the resting state releases high levels of the inhibitory neurotransmitter glutamate, while the release of glutamate is repressed by the hyperpolarization in the presence of light to trigger a downstream action potential by ganglion cells that convey signals to the brain. The calcium which enters the cell also activates GCAP, which activates guanylate cyclase (GC-1 and GC-2) to rapidly produce more cGMP, ending the hyperpolarization and returning the cell to its resting depolarized state. A protein called recoverin helps mediate the inactivation of the signal transduction cascade, returning rhodopsin to its preactivated state, along with the rhodopsin kinase Grk1. Phosphorylation of rhodopsin by Grkl causes arrestin to bind, helping to terminate the receptor activation signal. Dissociation and reassociation of retinal, dephosphorylation of rhodopsin and release of arrestin all return rhodopsin to its ready state, prepared once again to respond to light.VEGF，低氧Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. The increase in secreted biologically active VEGF protein from cells exposed to hypoxia is partly because of an increased transcription rate, mediated by binding of hypoxia-inducible factor-1 (HIF1) to a hypoxia responsive element in the 5'-flanking region of the VEGF gene. bHLH-PAS transcription factor that interacts with the Ah receptor nuclear translocator (Arnt), and its predicted amino acid sequence exhibits significantsimilarity to the hypoxia-inducible factor 1alpha (HIF1a) product. HLF mRNA expression is closely correlated with that of VEGF mRNA.. The high expression level of HLF mRNA in the O2 delivery system of developing embryos and adult organs suggests that in a normoxic state, HLF regulates gene expression of VEGF, various glycolytic enzymes, and others driven by the HRE sequence, and may be involved in development of blood vessels and the tubular system of lung. VEGF expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. HuR binds with high affinity and specificity to the VRS element that regulates VEGF mRNA stability by hypoxia. In addition, an internal ribosome entry site (IRES) ensures efficient translation of VEGF mRNA even under hypoxia. The VHL tumor suppressor (von Hippel-Lindau) regulates also VEGF expression at a post-transcriptional level. The secreted VEGF is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies.TSP-1诱导细胞凋亡As tissues grow they require angiogenesis to occur if they are to be supplied with blood vessels and survive. Factors that inhibit angiogenesis might act as cancer therapeutics by blocking vessel formation in tumors and starving cancer cells. Thrombospondin-1 (TSP-1) is a protein that inhibits angiogenesis and slows tumor growth, apparently by inducing apoptosis of microvascular endothelial cells that line blood vessels. TSP-1 appears to produce this response by activating a signaling pathway that begins with its receptor CD36 at the cell surface of the microvascular endothelial cell. The non-receptor tyrosine kinase fyn is activated by TSP-1 through CD36, activating the apoptosis inducing proteases like caspase-3 and p38 protein kinases. p38 is a mitogen-activated kinase that also induces apoptosis in some conditions, perhaps through AP-1 activation and the activation of genes that lead to apoptosis.Trka信号转导Nerve growth factor (NGF) is a neurotrophic factor that stimulates neuronal survival and growth through TrkA, a member of the trk family of tyrosine kinase receptors that also includes TrkB and TrkC. Some NGF responses are also mediated or modified by p75LNTR, a low affinity neurotrophin receptor. Binding of NGF to TrkA stimulates neuronal survival, and also proliferation. Pathways coupled to these responses are linked to TrkA through association of signaling factors with specific amino acids in the TrkA cytoplasmic domain. Cell survival through inhibition of apoptosis is signaled through activation of PI3-kinase and AKT. Ras-mediated signaling and phospholipase C both activate the MAP kinase pathway to stimulate proliferation.dbpb调节mRNAEndothelial cells respond to treatment with the protease thrombin with increased secretion of the PDGF B-chain. This activation occurs at the transcriptional level and a thrombin response element was identified in the promoter of the PDGF B-chain gene. A transcription factor called the DNA-binding protein B (dbpB) mediates the activation of PDGF B-chain transcription in response to thrombin treatment. DbpB is a member of the Y box family of transcription factors and binds to both RNA and DNA. In the absence of thrombin, endothelial cells contain a 50 kD form of dbpB that binds RNA in the cytoplasm and may play a role as a chaperone for mRNA. The 50 kD version of dbpB also binds DNA to regulate genes containing Y box elements in their promoters. Thrombin activation results in the cleavage of dbpB to a 30 kD form. The proteolytic cleavage releases dbpB from RNA in the nucleus, allowing it to enter the nucleus and binds to a regulatory element distinct from the site recognized by the full length 50 kD dbpB. The genes activated by cleaved dbpB include the PDGF B chain. Dephosphorylation of dbpB also regulates nuclear entry and transcriptional activation.RNA digestion in vitro can release dbpB in its active form, suggesting that the protease responsible for dbpB may be closely associated in a complex. Identification of the protease that cleaves dbpB, the mechanisms of phosphorylation and dephosphorylation, and elucidation of the signaling path by which thrombin induces dbpB will provide greater understanding of this novel signaling pathway.CARM1甲基化Several forms of post-translational modification regulate protein activities. Recently, protein methylation by CARM1 (coactivator-associated arginine methyltransferase 1) has been observed to play a key role in transcriptional regulation. CARM1 associates with the p160 class of transcriptional coactivators involved in gene activation by steroid hormone family receptors. CARM1 also interacts with CBP/p300 transcriptional coactivators involved in gene activation by a large variety of transcription factors, including steroid hormone receptors and CEBP. One target of CARM1 is the core histones H3 and H4, which are also targets of the histone acetylase activity of CBP/p300 coactivators. Recruitment of CARM1 to the promoter region by binding to coactivators increases histone methylation and makes promoter regions more accessible for transcription. Another target of CARM1 methylation is a coactivator it interacts with, CBP. Methylation of CBP by CARM1 blocks CBP from acting as a coactivator for CREB and redirects the limited CBP pool in the cell to be available for steroid hormone receptors. Other forms of post-translational protein modification such as phosphorylation are reversible in nature, but as of yet a protein demethylase is not known.CREB转录因子The transcription factor CREB binds the cyclic AMP response element (CRE) and activates transcription in response to a variety of extracellular signals including neurotransmitters, hormones, membrane depolarization, and growth and neurotrophic factors. Protein kinase A and the calmodulin-dependent protein kinases CaMKII stimulate CREB phosphorylation at Ser133, a key regulatory site controlling transcriptional activity. Growth and neurotrophic factors also stimulate CREB phosphorylation at Ser133. Phosphorylation occurs at Ser133 via p44/42 MAP Kinase and p90RSK and also via p38 MAP Kinase and MSK1. CREB exhibit deficiencies in spatial learning tasks, while flies overexpressing or lacking CREB show enhanced or diminished learning, respectively.TPO信号通路Thrombopoietin (TPO) binds to its receptor inducing aggregation and activation. TPO signals its growth regulating effects to the cell through several major pathways including MAPK (ERK and JNK), Protein Kinase C, and JAK/Stat.Toll-Like 受体The innate immune response responds in a general manner to factors present in invading pathogens. Bacterial factors such as lipopolysaccharides (LPS, endotoxin), bacterial lipoproteins, peptidoglycans and also CpG nucleic acids activate innate immunity as well as stimulating the antigen-specific immune response and triggering the inflammatory response. Members of the toll-like receptor (TLR) gene family convey signals stimulated by these factors, activating signal transduction pathways that result in transcriptional regulation and stimulate immune function. TLR2 is activated by bacterial lipoproteins, TLR4 is activated by LPS, and TLR9 is activated by CpG DNA; peptidoglycan recognition protein (PGRP) is activated bypeptidoglycan (PGN). The downstream signaling pathways used by these receptors are similar to that used by the IL-1 receptor, activating the IL-1 receptor associated kinase (IRAK) through the MyD88 adaptor protein, and signaling through TRAF-6 and protein kinase cascades to activate NF-kB and Jun. NF-kB and c-Jun activate transcription of genes such as the proinflammatory cytokines IL-1 and IL-12. Several recent reports have suggested that the functional outcomes of signaling via TLR2, TLR4 and PGRP are not equivalent. For example, while the LPS-induced,p38-dependent response was dependent upon PU.1 binding, the PGN-induced, p38 response was not. The intracelular receptor for PGN, PGRP is conserved from insects to mammals. In insects, PGRP activates prophenoloxidase cascade, a part of the insect antimicrobial defense system. Because mammals do not have the prophenoloxidase cascade, its function in mammals is unknown. However, it was suggested that an identical protein Tag7 was a tumor necrosis factor-like (TNF-like) cytokine.PGRP/Tag7 possesses cytotoxicity and triggers intranucleosomal DNA fragmentation in target cells in the same way as many known members of the TNF family. Fragmentation of DNA is one of the characteristics of apoptosis. The possibility that in another system, PGRP/Tag7 would induce NF-kB activation, as observed for TRAIL (TNF-related apoptosis-inducing ligand) receptors canot be ruled out.TNFR2 is the receptor for the 171 amino acid 19 kD TNF(beta) (a.k.a. lymphotoxin). TNF(beta) is produced by activated lymphocytes and can be cytotoxic to many tumor and other cells. In neutrophils, endothelial cells and osteoclasts TNF(beta) can lead to activation while in many other cell types it can lead to increased expression of MHC and adhesion molecules.TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) and also will bind TNF(beta). Upon binding TNF(alpha) a TNFR1+ cell is triggered to undergo apoptosis. This critical regulatory process is accomplished by activating the proteolytic caspase cascade that results in the degradation of many critical cellular proteinsIGF-1受体TNF/Stress相关信号TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 (See TNFR1 and TNFR2 Signaling Pathways) to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). Interaction of TNFR1 with TRADD leads to activation of NF-kB and apoptosis pathways, while interaction with TRAF2 has generally been thought to be involved in stress kinase and NF-kB activation but is not required for TNF to induce apoptosis. Activation of NF-kB is mediated by TRAF2 through the NIK kinase and also by RIP but the observation that TNF activates NF-kB in mice lacking TRAF2 indicates that TRAF-2 does not play an essential role in this process. Stress-activated protein kinases, also called JNKs, are a family of map kinases activated by cellular stress and inflammatory signals. Binding of TNF to the TNFR1 receptor activates the germinal center kinase (GCK) through the TNF adaptor Traf2, activating the map kinase MEKK1. Both GCK and MEKK1 interact with Traf2, andGCK is required for MEKK1 activation by TNF, but GCK kinase activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Tank increases the affinity of Traf2 for GCK to increase Map kinase activation by TNF. Once activated, MEKK1 stands at the top of a map kinase pathways leading to transcriptional regulation, including JNK phosphorylation of c-Jun to stimulate transcriptional activation by AP-1, a heterodimer of c-jun and fos or ATF proteins. The activation of the p38 Map kinase also contributes to AP-1 activation leading to the transcriptional activation of many stress and growth related genes. RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-kB activation. MEKK1 knockout mice support the role of MEKK1 in JNK activation in some cells but did not support MEKK1 dependent activation of NF-kB. Alternative redundant mechanisms may obscure the role of MEKK1 in NF-kB mechanisms. TNF activation of stress kinase pathways and downstream transcription factors may help to modulate the apoptotic pathways also activated by TNF.共刺激信号For a T cell to be activated by a specific antigen, the T cell receptor must recognize complexes of MHCI with the antigen on the surface of an antigen-presenting cell. T cells and the T cell receptor complex do not respond to antigen in solution, but even for the specific antigen they only respond to antigen-MHC-1 complexes on the cell surface. This interaction is necessary for T cell activation, but it is not sufficient. T cell activation also requires a co-stimulatory signal involving interaction of CD28 on the T cell with CD80 or CD86 (B7 family genes) on the antigen-presenting cell.CD28 activates a signal transduction pathway acting through PI-3K, Lck andGrb-2/ITK to provide its co-stimulatory signal for T cell activation. Another means to control T cell activation is by expressing factors that down-regulate T cell activation. Signaling by activated T cell receptors induces expression of CTLA-4, a receptor that opposes T cell activation. CTLA-4 has a higher affinity than CD28 for B7 proteins, terminating T cell activation. ICOS is a protein related to CD28 that is only expressed on activated T cells, and that provides another important co-stimulatory signal. The requirement for co-stimulatory signals provides additional control mechanisms that prevent inappropriate and hazardous T cell activation.。

常见信号通路

JNK生理功能
参与细胞凋亡的调控细胞存活肿瘤的形成机体的发育与分化
（三）p38信号转导通路
p38α：白细胞、肝、脾、骨髓中等高表达
p38β：脑和心脏中高泌器官中高表达
注： p38 α和 p38 β 具有不同的剪接体
重要的几种信号通路介绍
• • • • • • MAPK信号通路 JAK-STAT信号通路 Wnt信号通路 TGF- 信号通路 NF- B信号通路 PI3K-AKT信号通路
MAPK信号通路丝裂原活化蛋白激酶
MAPK信号级联反应
Stimulus
Growth factors, Mitogen, GPCR Raf, Mos, Tpl2
•
•
3个基因转录产物的选择性剪接产生10个JNK 亚型 (46kDa, 55kDa)；
同一基因编码的46kDa和55kDa亚型无明显的功能差异。
JNK信号通路MKK和MKKK
MKK (MAP2Ks) • MKK4 ( SEK1/MEK4/JNKK1/SKK1 )
• 主要激活JNK，但对p38也有活化作用
（二）JNK信号转导通路
• 是已知的应答最多样刺激的细胞信号转导途径之一 • JNK通过Thr-Pro-Tyr模体的磷酸化被激活
JNK:
• • • 人的JNK由3个基因 ( jnk1, jnk 2和 jnk3)编码； JNK1和JNK2广泛地在多种组织表达，而 JNK3 主要在脑、心脏与睾丸组织中表达 JNK家族成员间的同源性超过80%；
激活p38途径的物理、化学应激：
• 氧化应激 (巨噬细胞 )
• 低渗压 (HEK293细胞 ) • 紫外线辐射 (PC12细胞 ) • 低氧 (牛肺动脉成纤维细胞 ) • 循环扩张 (肾小球膜细胞 )

细胞信号通路大全

信号通路与免疫系统疾病
自身免疫疾病
自身免疫疾病患者体内免疫细胞信号通路异常激活，如T细胞、B细胞等信号通路，导致自身免疫反应过度。
炎症性疾病
炎症性疾病患者体内炎症细胞信号通路异常激活，如NF-κB、MAPK等信号通路，导致炎症反应过度或持续。
感染性疾病
感染性疾病患者体内病原微生物通过干扰免疫细胞信号通路，如细菌、病毒等，逃避免疫细胞的攻击。
PI3K-Akt信号通路
PI3K-Akt信号通路是细胞生存和增殖的关键信号转导途径。
PI3K-Akt信号通路在细胞生长、代谢、存活和凋亡等过程中发挥重要作用。当细胞受到生长因子、激素等刺激时，PI3K被激活，进而催化生成PIP3，后者与Akt结合并使其磷酸化，从而激活Akt。Akt可以进一步调控下游的靶蛋白，参与细胞增殖、迁移、代谢等过程。
JAK-STAT信号通路
JAK-STAT信号通路是细胞因子信号转导的重要途径之一。
JAK-STAT信号通路在细胞因子信号转导中发挥关键作用。当细胞因子与受体结合后，JAK被激活并催化受体酪氨酸磷酸化，进而招募并磷酸化STAT蛋白。STAT蛋白形成二聚体并进入细胞核，调控靶基因的表达，参与细胞生长、分化、免疫调节等过程。
信号通路的自调节
信号通路的正反馈调节
自调节的一种形式是正反馈调节，它通过增加某个关键信号分子的数量或活性，进一步增强自身的信号传递。例如，某些生长因子可以诱导自身受体的表达，形成一个正反馈环路，不断放大信号传递。
信号通路的负反馈调节
另一种自调节形式是负反馈调节，它通过降低某个关键信号分子的数量或活性，来抑制自身的信号传递。例如，某些激素可以通过诱导产生拮抗性激素或受体，从而抑制自身的信号传递。

细胞概念图：第3节：G蛋白偶联受体介导的信号转导

千里之行始于足下1途径一：激活离子通道的G 蛋白偶联受体所介导的信号通路G 蛋白偶联受体介导的信号转导受体：G 蛋白结构三个亚基组成G α：分子开关锚定在膜上G β、G γ：二聚体形式，锚定在膜上7次跨膜α螺旋（右图上）N 端在胞外、C 端在胞内激活的普遍机制（右图下）根据效应蛋白分类1、激活离子通道的G 蛋白偶联受体2、激活或抑制腺苷酸环化酶，以cAMP 为第二信使的G 蛋白偶联受体3、激活磷脂酶C ，以IP 3和DGA 作为双信使的G 蛋白偶联受体三类方式比较千里之行始于足下2图⑤ 图⑥典型例子心肌细胞M 乙酰胆碱受体激活G 蛋白开启K +通道附图p168（下图⑤）Gt 蛋白偶联的光敏感受体的活化诱发cGMP 门控阳离子通道的关闭附图p168（下图⑥）第二信使：cGMP千里之行始于足下 3途径二：激活或抑制腺苷酸环化酶的G 蛋白偶联受体环化酶的G 蛋白偶联受体刺激AC 的物质肾上腺素、胰高血糖素、促肾上腺皮质激素受体：刺激性激素受体（Rs ），Gs α抑制AC 的物质前列腺素、腺苷受体：抑制性激素受体（Ri ），Gi αACAC 结构12次跨膜蛋白C 端与N 端均在细胞内胞质侧有两个大的相似的结构域，跨膜区有两个整合结构域AC 功能在Mg 2+或Mn 2+存在下，催化ATP 生成cAMP蛋白激酶A （PKA ）未激活状态2个调节亚基与2个催化亚基结合激活状态激活物：cAMP调节亚基与催化亚基分开图⑦4 千里之行始于足下图⑧ 图⑨图115千里之行始于足下6 千里之行始于足下千里之行始于足下7激活磷脂酶C 、以IP 3和DGA 作为双信使G 蛋白偶联受体介导的信号通路图10第三条途径双信使(图10)来源磷脂酰肌醇(PI)代谢(图11)双信使介绍肌醇三磷酸(IP 3)机制与内质网上IP 3R 结合，开放Ca 2+通道功能引发贮存在内质网中的Ca 2+转移到细胞质基质中，使胞质中Ca 2+浓度升高二酰甘油(DAG)机制激活蛋白激酶C(PKC)降解DAG 激酶磷酸化后进入磷脂肌醇代谢DAG 脂酶水解成单酰甘油DAG 的维持原因细胞增殖、分化需要维持DAG 活性生成途径磷脂酶催化膜上磷脂酰胆碱断裂产生DAG蛋白激酶C(PKC)(图12)激活的信号分子与细胞分泌、肌肉收缩、细胞增殖、分化有关的信号分子作用途径一：磷酸化MAP 激酶途径二：磷酸化一种抑制蛋白8 千里之行始于足下千里之行始于足下9激活离子通道的G 蛋白偶联受体激活/抑制腺苷酸环化酶的G 蛋白偶联受体激活磷脂酶C 的G 蛋白偶联受体心肌细胞上K +通道的启闭视杆细胞的光受体启闭效应蛋白 G 蛋白 PDE 腺苷酸环化酶(AC) 磷脂酶C(PLC)第二信使无 cGMP cAMP IP 3、DAG生物学功能调节心肌细胞内外K +浓度，影响心肌收缩频率生物感光调节肝细胞和肌细胞糖原代谢，对真核细胞基因表达调控调节基因表达，与肌肉收缩、细胞增殖、分化有关图1210 千里之行始于足下。

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