细胞通讯系统五大分子信号通路共35页

（三）、细胞的信号分子与受体 ）、细胞的信号分子与受体
信号分子 激素 肾上腺素 胰岛素 雌二醇 局部介质 表皮生长因子 组胺 NO 神经递质 乙酰胆碱 Γ-氨基丁酸 氨基丁酸 接触依赖性信号 分子（ ） 分子（δ） 神经终末 神经终末 预定神经元 胆碱衍生物 谷氨酸衍生物 跨膜蛋白 兴奋性神经递质 抑制性神经递质 抑制相邻细胞以与信号细胞相同的方 式分化 不同细胞 肥大细胞 神经细胞 蛋白质 组氨酸衍生物 可溶性气体 刺激上皮细胞和多种细胞的增殖 扩张血管，增加渗透， 扩张血管，增加渗透，有助发炎 引起平滑肌细胞松驰， 引起平滑肌细胞松驰，调节神经细胞 肾上腺 胰腺β细胞 胰腺 细胞 卵巢 酪氨酸的和衍生物 蛋白质 类固醇 增加血压、 增加血压、心律 刺激肝细胞葡萄糖摄取、蛋白质合成 刺激肝细胞葡萄糖摄取、 诱导和维持雌性第二性征 合成或分泌位点 化学性质 生理功能
4、信号通路 、
信号通路： 信号通路：signaling pathway，细胞接受外界信号，通 ，细胞接受外界信号， 过一整套特定的机制，将胞外信号转导为胞内信号， 过一整套特定的机制，将胞外信号转导为胞内信号， 最终调节特定基因的表达，引起细胞的应答反应，这 最终调节特定基因的表达，引起细胞的应答反应， 系列称之。 系列称之。 细胞识别正是通过各种不同的信号通路实现的。 细胞识别正是通过各种不同的信号通路实现的。
2、受体 、
受体： 识别和选择性结合某种配 受体：receptor，是一种能够识别和选择性结合某种配 ，是一种能够识别和选择性结合 体（信号分子）的大分子，当与配体结合后，通过信 信号分子）的大分子，当与配体结合后， 号转导作用将胞外信号转换为胞内物理或化学的信号， 号转导作用将胞外信号转换为胞内物理或化学的信号， 以启动一系列过程，最终表现为生物学效应。 以启动一系列过程，最终表现为生物学效应。 受体多为糖蛋白， 受体多为糖蛋白，包括与配体结合区域及产生效应区 域。且均有特异性。 且均有特异性。 根据受体存在部位， 根据受体存在部位，分细胞内受体和细胞表面受体

细胞生物学课件章细胞通信和信号
FUNCTIONS OF CELL MUNICATION
Gene transcription Cell proliferation Cell survival Cell death Cell differentiation Cell function Cell motility Immune responses
Controls on Cytosolic Calcium
(三)其她G蛋白偶联型受体
1、化学感受器中得G蛋白 • 存在于嗅觉和味觉化学感受器中,类型繁多,不同细胞具有
不同得受体,感受不同得气味。 • 气味分子与G蛋白偶联型受体结合,可激活腺苷酸环化酶,
产生cAMP,开启cAMP门控阳离子通道(cAMP-gated cation channel),引起钠离子内流,膜去极化,产生神经冲动, 最终形成嗅觉或味觉。
Chemical synapse
Acetylcholine receptor
Three conformation of the acetylcholine receptor
Ion-channel linked receptors in neurotransmission
二、G蛋白耦联型受体
• 通过调节cAMP得浓度,将细胞外 信号转变为细胞内信号。
主要组分: • ①激活型受体(Rs)或抑制型受体
(Ri); • ②活化型调节蛋白(Gs)或抑制型
调节蛋白(Gi);
G-protein linked receptor
• ③ 腺苷酸环化酶: 跨膜12次。在Mg2+ 或Mn2+得存在下, 催化ATP生成 cAMP。
大家有疑问的，可以询问和交流
可以互相讨论下，但要小声点

1PPAR信号通路：过氧化物酶体增殖物激活受体(PPARs)是与维甲酸、类固醇和甲状腺激素受体相关的配体激活转录因子超家族核激素受体成员。

它们作为脂肪传感器调节脂肪代谢酶的转录。

PPARs由PPARα、PPARβ和PPARγ3种亚型组成。

PPARα主要在脂肪酸代谢水平高的组织，如：肝、棕色脂肪、心、肾和骨骼肌表达。

他通过调控靶基因的表达而调节机体许多生理功能包括能量代谢、生长发育等。

另外，他还通过调节脂质代谢的生物感受器而调节细胞生长、分化与凋亡。

PPARa同时也是一种磷酸化蛋白，他受多种磷酸化酶的调节包括丝裂原激活蛋白激酶(ERK-和p38．MAPK)，蛋白激酶A和C(PKA，PKC)，AMPK和糖原合成酶一3(GSK3)等调控。

调控PPARa生长信号的酶报道有MAPK、PKA和GSK3。

PPARβ广泛表达于各种组织，而PPARγ主要局限表达在血和棕色脂肪，其他组织如骨骼肌和心肌有少量表达。

PPAR-γ在诸如炎症、动脉粥样硬化、胰岛素抵抗和糖代谢调节，以及肿瘤和肥胖等方面均有着举足轻重的作用，而其众多生物学效应则是通过启动或参与的复杂信号通路予以实现。

鉴于目前人们对PPAR—γ信号通路尚不甚清，PPARs通常是通过与9-cis维甲酸受体(RXR)结合实现其转录活性的。

2MAPK信号通路:mapk简介:丝裂原激活蛋白激酶（mitogen—activatedproteinkinase，MAPK）是广泛存在于动植物细胞中的一类丝氨酸/苏氨酸蛋白激酶。

作用主要是将细胞外刺激信号转导至细胞及其核内，并引起细胞的生物化学反应（增殖、分化、凋亡、应激等）。

MAPKs家族的亚族:ERKs（extracellularsignalregulatedkinase) ：包括ERK1、ERK2。

生长因子、细胞因子或激素激活此通路，介导细胞增殖、分化。

JNKs(c-JunN-terminalkinase)包括JNK1、JNK2、JNK3。

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.。

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。

Wnt受体，其胞外N端具有富含半胱氨酸的结构 域，Frz作用于胞质内的蓬乱蛋白（Dsh），Dsh 能切断β-catenin的降解途径，从而使β-catenin在 细胞
质中积累，并进入细胞核，与T细胞因子 （TCF/LEF）相互作用，调节靶基因的表达。 Hedgehog信号通路 Hedgehog是一种共价结合胆固醇的分泌性蛋
u通过自我磷酸化激活并进而磷酸化其底物Cos2 与Sufu而将Hh信号传递至下游。这一过程将促使 全长的转录因子Ci155由Cos2及Sufu动态解离出 来并进入细胞
核内启动目的基因的表达。这项研究表明，细胞 能够通过动态调节Fu二聚化及其激酶活性而感应 不同水平的Hh信号。另外也提示了Hh信号通路 成员如何通过磷酸化影响他们的活
的Bouras等科学家发表文章称，他们发现了 Notch信号途径在调控乳房干细胞功能和乳房上 皮层级当中所发挥的作用。 Notch是一种跨膜的受体，它们广泛存在于
各种动物细胞中。Notch信号途径对于多种组织 和细胞命运非常重要，包括表皮、神经、血液和 肌肉等。在本期的封面文章中，研究人员发现， 敲除MaSC富集细胞群当中的规
癌细胞中保持高活性的通路。他们还指出，Wnt 信号转导通路与恶性癌症的发生有密切关系 “基因突变激活Wnt信号通路一般会导致结肠癌 的发生，肺癌通常是由其他基因变
异引起，所以我们对于Wnt细胞信号转导通路与 肺癌有莫大关系也非常惊讶。”论文通讯作者琼 马萨格博士表示。[详细] 我国科学家在Hedgehog信号通路传递研究方
向取得新进展 CellResearch在线发表了中科院上海生命科学研 究院生化与细胞所赵允和张雷研究组在研究 Hedgehog信号通路传递方面的新进展。通过研 究揭
示，Hh浓度梯度信号所引发的Smo磷酸化水平的 升高，能够通过Smo与Cos2之间的动态相互作 用将Cos2/Fu复合物招募到质膜上，从而诱导Fu 二聚化。二聚化的F

• 作用：通过磷酸化调节蛋白质的活性。
Protein kinases
五、胞间通信的主要类型
• （一）细胞间隙连接 • 连接子中央为直径1.5nm的亲水性孔道，允
许小分子如Ca2+、cAMP通过。 • 作用：协同相邻细胞对外界信号的反应，
如可兴奋细胞的电耦联现象(电紧张突触)。
connexon
（二）膜表面分子接触通讯
• 类型：①多种神经递质、肽类激素和趋化因子受 体，②味觉、视觉和嗅觉感受器。
• 相关信号途径：cAMP途径、磷脂酰肌醇途径。
G-protein linked receptor
• 三聚体GTP结合蛋白，即，G蛋白： • 组成：αβγ，α和γ属脂锚定蛋白。 • 作用：分子开关。α亚基结合GDP失活，结
Adenylate cyclase
• ④蛋白激酶A（Protein Kinase A，PKA）： 由两个催化亚基和两个调节亚基组成。
•cAMP与调节亚基结合，使调节亚基和催化亚基解离，释放出催化亚基， 激活蛋白激酶A的活性。
• ⑤环腺苷酸磷酸二酯酶(PDE)：降解cAMP 生成5’-AMP，终止信号。
• 即细胞识别，如：精子和卵子之间的识 别，T与B淋巴细胞间的识别。
（三）化学通讯
• 细胞分泌一些化学物质（如激素）至细胞 外，作为信号分子作用于靶细胞，调节其 功能，可分为4类。
• 内分泌：内分泌激素随血液循环输至全身，作用 于靶细胞。特点：①低浓度（10-8-10-12M ），② 全身性，③长时效。
• 细胞对信号的反应不仅取决于其受体的特 异性，而且与细胞的固有特征有关。
– 相同信号可产生不同效应：如Ach可引起骨骼肌 收缩、心肌收缩频率降低，唾腺细胞分泌。

第七章细胞通讯与信号传递第一节细胞通讯与细胞识别多细胞生物是一个繁忙而有序的细胞社会，这种社会性的维持不仅依赖于细胞的物质代谢，还有赖于细胞通讯与信号传递，从而以不同的方式协调它们的行为，诸如细胞生长、分裂、死亡、分化及其各种生理功能。

一、细胞通讯细胞通讯（cell communication)是指一个细胞发出的信息通过介质传递到另一个细胞产生相应的反应。

细胞间的通讯对于多细胞生物体的发生和组织的构建，协调细胞的功能，控制细胞的生长和分裂是必需的。

细胞以三种方式进行通讯：（1）细胞通过分泌化学信号进行细胞间相互通讯，这是多细胞生物包括动物和植物最普遍采用的通讯方式；（2）细胞间接触性依赖的通讯（contact-dependent signaling)，细胞间直接接触，通过与质膜结合的信号分子影响其他细胞；（3）细胞间形成间隙连接使细胞质相互沟通，通过交换小分子来实现代谢偶联或电偶联（见第四章有关间隙连接部分）。

细胞分泌化学信号的作用方式可分为：（1）内分泌（endocrine)，由内分泌细胞分泌信号分子（激素）到血液中，通过血液循环运送到体内各部位，作用于靶细胞。

（2）旁分泌（paracrine)。

细胞通过分泌局部化学介质到细胞外液中，经过局部扩散作用于邻近靶细胞。

这对创伤或感染组织刺激细胞增殖以恢复功能具有重要意义。

（3）自分泌（autocrine)。

细胞对自身分泌的物质产生反应。

自分泌信号常见于病理条件下，如肿瘤细胞合成和释放生长因子刺激自身，导致肿瘤细胞的增殖失控。

（4）通过化学突触传递神经信号（neur onal signaling)。

当神经元细胞在接受环境或其他神经细胞的刺激后，神经信号通过动作电位的形式沿轴突以高达100m/s的速度传至末梢，刺激突触前突起终末分泌化学信号（神经递质或神经肽），快速扩散（不到千分之一秒）作用于相距50nm的突触后细胞，影响突触后膜，实现电信号-化学信号-电信号转换和传导。

细胞信号通路⼤全1 PPAR信号通路：过氧化物酶体增殖物激活受体( PPARs) 是与维甲酸、类固醇和甲状腺激素受体相关的配体激活转录因⼦超家族核激素受体成员。

它们作为脂肪传感器调节脂肪代谢酶的转录。

PPARs由PPARα、PPARβ和PPARγ 3种亚型组成。

PPARα主要在脂肪酸代谢⽔平⾼的组织，如：肝、棕⾊脂肪、⼼、肾和⾻骼肌表达。

他通过调控靶基因的表达⽽调节机体许多⽣理功能包括能量代谢、⽣长发育等。

另外，他还通过调节脂质代谢的⽣物感受器⽽调节细胞⽣长、分化与凋亡。

PPARa同时也是⼀种磷酸化蛋⽩，他受多种磷酸化酶的调节包括丝裂原激活蛋⽩激酶( ERK-和p38．M APK) ，蛋⽩激酶A和C( PKA，PKC) ，AM PK和糖原合成酶⼀3( G SK3) 等调控。

调控PPARa⽣长信号的酶报道有M APK、PKA和G SK3。

PPARβ⼴泛表达于各种组织，⽽PPAR γ主要局限表达在⾎和棕⾊脂肪，其他组织如⾻骼肌和⼼肌有少量表达。

PPAR-γ在诸如炎症、动脉粥样硬化、胰岛素抵抗和糖代谢调节，以及肿瘤和肥胖等⽅⾯均有着举⾜轻重的作⽤，⽽其众多⽣物学效应则是通过启动或参与的复杂信号通路予以实现。

鉴于⽬前⼈们对PPAR—γ信号通路尚不甚清，PPARs通常是通过与9-cis维甲酸受体(R X R)结合实现其转录活性的。

2 MAPK信号通路:mapk简介:丝裂原激活蛋⽩激酶（mitogen—activated protein kinase，MAPK）是⼴泛存在于动植物细胞中的⼀类丝氨酸/苏氨酸蛋⽩激酶。

作⽤主要是将细胞外刺激信号转导⾄细胞及其核内，并引起细胞的⽣物化学反应（增殖、分化、凋亡、应激等）。

MAPKs家族的亚族 :ERKs（extracellular signal regulated kinase)：包括ERK1、ERK2。

⽣长因⼦、细胞因⼦或激素激活此通路，介导细胞增殖、分化。

JNKs(c-Jun N-terminal kinase)包括JNK1、JNK2、JNK3。

细胞信号传导通路
细胞信号传导通路是细胞内外信息传递的重要机制，它调控了
细胞的生长、分化和代谢。

本文将从细胞表面受体的激活、信号
传导分子的参与以及信号的响应等方面来探讨细胞信号传导通路。

1. 细胞表面受体的激活
细胞信号传导的起点通常是细胞膜上的受体蛋白，受体可分为
离子通道受体、酶联受体和GPCR等多种类型。

当外界信号分子（如激素或神经递质）与受体结合时，受体会发生构象变化，从
而激活下游信号传导分子。

2. 信号传导分子的参与
激活的受体将信号传递给下游分子，这些分子可以是激活的酶、离子通道或某些特定的细胞内信号传导蛋白。

典型的信号传导分
子包括蛋白激酶、蛋白磷酸酶、蛋白激酶激活受体和G蛋白等。

3. 信号的响应
细胞信号传导通路的最终目的是调控细胞的生理反应和功能。

信号的响应可以通过各种机制实现，例如细胞凋亡、基因表达的
调控、细胞增殖和分化等。

4. 细胞信号传导通路的调节
为了维持体内的稳态，细胞信号传导通路会受到多种调节因素的影响。

这些调节因素可以包括其他外界信号分子的参与、负反馈和正反馈机制的调控等。

此外，异常的细胞信号传导通路还与多种疾病的发生和发展密切相关。

细胞信号传导通路在生物体中发挥着重要的作用，它调节了细胞的生理功能和适应机制。

对于解析细胞信号传导通路的机制和调控方式，有助于深入理解疾病的发生机制，并为相关疾病的诊断和治疗提供新的思路。

相信随着研究的深入，细胞信号传导通路的奥秘将逐步揭示出来，为生命科学的发展做出更大的贡献。

1 PPAR信号通路：过氧化物酶体增殖物激活受体( PPARs) 是与维甲酸、类固醇和甲状腺激素受体相关的配体激活转录因子超家族核激素受体成员。

它们作为脂肪传感器调节脂肪代谢酶的转录。

PPARs由PPARα、PPARβ和PPARγ 3种亚型组成。

PPARα主要在脂肪酸代谢水平高的组织，如：肝、棕色脂肪、心、肾和骨骼肌表达。

他通过调控靶基因的表达而调节机体许多生理功能包括能量代谢、生长发育等。

另外，他还通过调节脂质代谢的生物感受器而调节细胞生长、分化与凋亡。

PPARa同时也是一种磷酸化蛋白，他受多种磷酸化酶的调节包括丝裂原激活蛋白激酶( ERK-和p38．M APK) ，蛋白激酶A和C( PKA，PKC) ，AM PK和糖原合成酶一3( G SK3) 等调控。

调控PPARa生长信号的酶报道有M APK、PKA和G SK3。

PPARβ广泛表达于各种组织，而PPAR γ主要局限表达在血和棕色脂肪，其他组织如骨骼肌和心肌有少量表达。

PPAR-γ在诸如炎症、动脉粥样硬化、胰岛素抵抗和糖代谢调节，以及肿瘤和肥胖等方面均有着举足轻重的作用，而其众多生物学效应则是通过启动或参与的复杂信号通路予以实现。

鉴于目前人们对PPAR—γ信号通路尚不甚清，PPARs 通常是通过与9-cis维甲酸受体( RXR)结合实现其转录活性的。

2 MAPK信号通路:mapk简介:丝裂原激活蛋白激酶（mitogen—activated protein kinase，MAPK）是广泛存在于动植物细胞中的一类丝氨酸/苏氨酸蛋白激酶。

作用主要是将细胞外刺激信号转导至细胞及其核内，并引起细胞的生物化学反应（增殖、分化、凋亡、应激等）。

：包括ERK1、MAPKs家族的亚族 :ERKs（extracellular signal regulated kinase)ERK2。

生长因子、细胞因子或激素激活此通路，介导细胞增殖、分化。

JNKs(c-Jun N-terminal kinase)包括JNK1、JNK2、JNK3。

③ 气体性信号分子：NO。
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2．受体（receptor）
受体：一种能够识别和选择性结合某种配体(信号 分子)的大分子。结合配体后，通过信号转导 (signal transduction) 作用将胞外信号转换为 胞内化学或物理的信号，启动一系列过程，最终 表现为生物学效应。
特征： 多为糖蛋白； 至少包括两个功能区域（受体结合区，效应区）。
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结构： C端:激素结合位点； 中 部 : DNA/Hsp90 结
合位点：富含Cys、 具锌指结构 N端:转录激活结构 域。
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2 甾类激素分子通过胞内受体的信号传导过程
①经简单扩散跨膜进入胞内； ②结合受体，形成激素—受体
复合物； ③ 受 体 构 象 改 变 ， 结 合 DNA 能
力增强； ④穿过核孔进入核内； ⑤ 活），调节基因表达。
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甾类激素作为信号诱导基因活化的两个阶段：
初级反应阶段：直接活化少数特殊基因的转录，发 生迅速；
次级反应阶段：由初级反应的产物再活化其他基因 产生，以放大初级反应，较缓慢。
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3. NO“明星信号分子”
体内NO的特性 ：
一种自由基性质的气体，具脂溶性，可快速扩散 过质膜，到达邻近靶细胞发挥作用（局部介质）。 NO生成部位：血管内皮细胞和神经细胞。
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㈠ 细胞通讯
• 细胞通讯 (cell communication) ：是指 一个细胞发出的信息通过介质传递到另 一个细胞产生相应反应的过程。
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种类
分泌化学信号的通讯； 接触性依赖的通讯 (contact-dependent signaling)； 通过间隙连接的通信。
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1 分泌化学信号的通讯
• 细胞信号通路(signaling pathway)：细胞接受 外界信号，通过一套特定的机制，将胞外信号转 导为胞内信号，最终调节特定基因的表达，引起 细胞的应答反应，这种反应系列称之为细胞信号 通路。

Cell Signalling Pathways--Michael J. Berridge--module 2 胞内信号通路可分为两类，大多数的信号通路受细胞表面的胞外信号刺激，通常以化学信号的形式，如神经递质、激素及生长因子等；其他类的信号通路是由细胞内产生的信号激活的。

胞内信号主要来自内质网或代谢物。

一、环腺苷酸信号通路（Cyclic AMP signalling pathway）环腺苷酸是广泛存在的一种第二信使，其形成依赖于GPCR的活化，GPCR通过异质三聚体激活放大器AC（腺苷酸环化酶）。

cAMP的信号效应器有PKA、EPACs等可激活小GTP连接蛋白Rap1及环核苷酸门控通道（CNGCs），这些效应器负责进行cAMP信号功能。

cAMP 的许多功能取决于PKA的准确定位，而A激酶锚定蛋白（AKAPs）家族约定了PKA及其他许多信号组分的细胞定位。

Cyclic AMP formation环腺苷酸的形成可被许多细胞刺激活化，主要是神经递质和激素，这些刺激可被G蛋白偶联受体通过异质三聚体G蛋白检测到。

在腺苷酸环化酶刺激下，外部刺激结合到G蛋白偶联受体上，作为鸟苷酸交换因子（GEF）用GTP替代GDP，从而使得异质三聚体G蛋白分裂成Gβᵞ和Gα亚基。

Gα亚基和GTP的复合体激活腺苷酸环化酶，然而抑制性GαGTP 抑制AC。

Ｇα亚基具有GTP酶活性，可水解GTP成GDP，因而停止其对AC的作用。

Adenylyl cyclase (AC)AC家族由十个亚型组成，前九个为膜结合的，另外一个是水溶性的。

AC1-9的域结构具有两个含六个转膜区的区域。

大的细胞浆域C1和C2含有催化区，形成异质二聚体使得ATP 转化成AMP。

Cyclic AMP signalling effectorsEPACs、CNGCs等，cAMP的大多数作用都是通过PKA发挥作用的。

Protein kinase A (PKA)PKA由两个调节亚基（R）和两个催化亚基（C）组成。

通过放射性同位素标记细胞内的分子，追踪 其在信号通路中的动态变化，从而揭示信号 通路的调控机制。
荧光共振能量转移（ FRET）技术
实时监测细胞内分子间的相互作用，以揭示 信号通路中分子的动态调控过程。
细胞信号通路的细胞生物学研究技术
荧光显微镜技术
观察细胞内分子的定位与动态变化，以解析信号通路在细胞亚结构 中的调控机制。
细胞信号通路的异常往 往与疾病的发生和发展 密切相关。因此，对细 胞信号通路的研究有助 于深入了解生命活动的 调控机制，为疾病的预 防和治疗提供新思路。
细胞信号通路的分类
• 细胞信号通路可根据不同的标准进行分类，如传递方式、 传递距离以及受体类型等。以下是几种常见的分类方式
细胞信号通路的分类
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针对免疫疾病中紊乱的细胞信号 通路进行干预，例如使用JAK抑制 剂来抑制异常活化的JAK/STAT信 号通路，以治疗类风湿性关节炎 等免疫疾病。
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CATALOGUE
细胞信号通路的研究方法与技术
细胞信号通路的分子生物学研究技术
基因敲除技术
通过特定手段使特定基因失活，以研究该基因在细胞信号通路中 的作用。
细胞信号通路的重要性
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细胞信号通路在生命活 动中具有至关重要的作 用，它们参与调节许多 生理过程，如
细胞生长与分化：通过 激活或抑制特定基因表 达，信号通路能够调控 细胞的生长和分化命运 。
免疫应答：信号通路在 免疫细胞中参与抗原识 别、炎症反应以及免疫 细胞活化等过程。
神经传导：在神经细胞 中，信号通路介导神经 递质的释放与接收，实 现神经元之间的信息传 递。
促进合成生物学、人工智能和细胞信号通路研究领域的跨学科合作 ，推动技术创新和成果转化。

受体recepter;
受体将信号转变为细胞内信号-第 二信使
胞内信号的转导途径，最终转化为 细胞的各种复杂的生物学效应。
信号分子的失活引起细胞反应的终 止
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第一节 细胞外信号
第一信使:由细胞分泌的、能够调节机体机体功能的一大类生物活性物质，是 细胞间通讯的信号。
主要是蛋白质、肽类、氨基酸及其衍生物、类固醇激素、NO等。 与细胞膜上或胞内特定的受体结合后，后者将接收到得信息转导给胞浆或细
相互激活 激活具有SH2结构域的蛋白并
使之激活，传递信号 主要介导细胞生长和分化，产
生效应过程较慢
3、G蛋白耦联的受体（G蛋白-鸟苷酸结合蛋16白（guanine nucleotide－binding protein） 存在于细胞膜上，神经递质、激素、肽类和胺类的受体，与G蛋白耦联。 结构： 由一条多肽链组成，其中带有7个疏水越膜区域 氨基末端朝向细胞外，羧基末端则朝向细胞内基质 氨基末端有糖基化的位点，羧基末端有两个在蛋白激酶催化下发生磷酸化 的位点 ，与受体活性调控有关。
细胞内信使：受体激活后在细胞内产生的、能介导信号转导的活性物质，又称 第二信使（sencond messenger）。 cAMP，cGMP，DAG, IP3, Ca2+
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一、cAMP信使体系 腺苷酸环化酶与cAMP
腺苷酸环化酶 adenylate cyclase,AC； G蛋白的效应蛋白之一，是cAMP信 号传递系统的关键酶；
胞核中的功能反应体系，从而启动细胞产生效应。
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细胞外信号分类： 根据信号特点和作用方式 激素 神经递质 局部化学介质 根据效应： 激动剂 拮抗剂 根据信号的性质 水溶性信号 脂溶性信号
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第一节 细胞外信号