细胞常见信号通路图片合集

细胞凋亡信号调节

DNA

片段化

(2004-6-4)

·

细胞凋亡

DNA

片段化与组织稳态的机理

(2004-6-4)

·

反义核酸的作用机理

---RNA polymerase III

(2004-6-4)

·

抗原递呈与处理信号图

(2004-6-4)

Antigen

依赖的

B

细胞激活

(2004-6-4)

·

Anthrax Toxin Mechanism of Action

(2004-6-4)

·

血管紧张素转换酶

2

调节心脏功能

(2004-6-4)

·

Angiotensin II

介 导

JNK

信号通路的激活

(2004-6-4)

·

Alternative Complement Pathway

(2004-6-4)

·

Alpha-synuclein

和

Parkin

在怕金森病中的作用< /p>

(2004-6-4)

·

ALK

在 心肌细胞中的功能图

(2004-6-4)

AKT

信号通路

(2004-6-4)

AKAP95

在有丝分裂中的作用图

(2004-6-4)

·

Ahr

信 号转导图

(2004-6-4)

·

Agrin

突触后的功能图

(2004-6-4)

·

ADP-Ribosylation

因子

(2004-6-4)

·

淋巴细胞粘附分子信号图

(2004-6-4)

·

Adhesion and Diapedesis of Lymphocytes

(2004-6-4)

·

Adhesion and Diapedesis of Granulocytes

(2004-6-4)

·

急性心肌梗死信号转导图

(2004-6-4)

src

蛋白质激活图

(2004-6-4)

PKC

与

G

(2004-6-4)

cAMP

依赖的

CSK

抑制

T

细胞功能示意图

(2004-6-4)

·

PKA

功能示意图

< br>

(2004-6-4)

< /p>

·

一氧化氮（

NO

）在心脏中的功能示意图

(2004-6-4)

·

RelA

在细胞核内乙酰化和去乙酰化

(2004-6-4)

actin

肌丝

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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 actin alterations 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

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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 Aug 15;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), 790-3

Falet 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), 1347-56

Robinson, R.C. et al. (2001) Crystal structure of Arp2/3 complex. Science 294(5547), 1679-84

Weeds A, Yeoh S. Structure. Action at the Y-branch. Science. 2001 Nov 23;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 signaling

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WNT

信号转导

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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 the

WNV-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)

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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

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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 of dietary 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

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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

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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 rod cells, a member of the G-protein coupled receptor

gene family. Rhodopsin remains the only GPCR whose structure has been resolved at high resolution. Rhodopsin

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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

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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 significant similarity

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

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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

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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

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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

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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

mRNA

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Endothelial 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.

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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

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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

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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

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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

精选

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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

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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 by peptidoglycan (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,

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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

信号通路

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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

信号通路

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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 proteins

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IGF-1

受体

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TNF/Stress

相关信号

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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, and GCK 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.

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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

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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

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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 and Grb-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.

Th1/Th2

细胞分化

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Helper T cells are found in two distinct cell types, Th1 and Th2, distinguished by the cytokines they produce and

respond to and the immune responses they are involved in. Th1 cells produce pro-inflammatory cytokines like

IFN-g, TNF-b and IL-2, while Th2 cells produce the cytokines IL-4, IL-5, IL-6 and IL-13. The cytokines produced

by Th1 cells stimulate the phagocytosis and destruction of microbial pathogens while Th2 cytokines like IL-4

generally stimulate the production of antibodies directed toward large extracellular parasites (see

揑

L-4

Signaling Pathway?. IL-5 stimulates eosinophil responses, also part of the immune response toward large

extracellular parasites (see

揑

L-5 Signaling Pathway?

Th1 and Th2 are produced by differentiation from a non- antigen exposed precursor cell

type, Thp. Exposure of Thp cells to antigen by antigen- presenting cells may result in their

differentiation to Th0 cells, not yet committed to become either Th1 or Th2 cells, although

the existence of Th0 cells is controversial. Cells committed as either Th1 and Th2 cells are

called polarized, whether they are effector cells actively secreting cytokines or are memory

cells. The stimulation of Thp cells by exposure to antigen- presenting cells induces the

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proliferation of undifferentiated cells, and their expression of IL-2 and IL-2 receptor. The

differentiation of Th1 cells and Th2 cells depends on the cytokines they are exposed to.

IL-12 causes Th1 differentiation and blocks Th2 cell production (see

揑

L12 and Stat4

Dependent Signaling Pathway in Th1 Development?pathway), while IL-4 causes Th2

differentiation and antagonizes Th1 development. IL-18 also induces Th1 differentiation

(See

揑

L-18 signaling pathway?. Polarized Th1 and Th2 cells also express distinct sets of

chemokine receptors that further modify their homing and other cellular responses (see

揝

elective expression of chemokine receptors during T-cell polarization?pathway). Improved

understanding of Th1 and Th2 differentiation will improve our overall understanding of the

immune system, its response to infection and aberrant responses that lead to disease.

TGF beta

信号转导

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TGF-beta regulates growth and proliferation of cells, blocking growth of many cell types. The TGF-beta receptor

includes type 1 and type 2 subunits that are serine-threonine kinases and that signal through the SMAD family

of transcriptional regulators. Defects in TGF-beta signaling, includes mutation in SMADs, have been associated

with cancer in humans. Prior to activation, receptor regulated SMADs are anchored to the cell membrane by

factors like SARA (SMAD Anchor for Receptor Activation) that brings the SMADs into proximity of the TGF

receptor kinases. Binding of TGF induces phosphorylation and activation of the TGF-beta R1 receptor by the

TGF-beta R2 receptor. The activated TGF-beta R1 phosphorylates SMAD2 and SMAD3, which bind to the SMAD4

mediator to move into the nucleus and form complexes that regulate transcription. SMADs regulate

transcription in several ways, including binding to DNA, interacting with other transcription factors, and

interacting with transcription corepressors and coactivators like p300 and CBP. SMAD-7 represses signaling by

other SMADs to down-regulate the system. Other signaling pathways like the MAP kinase-ERK cascade are

activated by TGF-beta signaling, modulate SMAD activation. SnoN also regulates TGF-beta signaling, by binding

to SMADs to block transcriptional activation. TGF-beta signaling causes degradation of SnoN, releasing SMADs

to regulate transcription, and also activates expression of SnoN, to down-regulate SMAD signaling at later

times.

端粒、端粒酶与衰老

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Telomeres, which define the ends of chromosomes, consist of short, tandemly repeated DNA sequences loosely

conserved in eukaryotes. Telomerase is a ribonucleoprotein complex ( we only show a few of the components in

this illustration) which in vitro recognizes a single-stranded G-rich telomere primer and adds multiple telomeric

repeats to its 3-prime end by using an RNA template. Telomerase may also have a role in de novo formation of

telomeres. Telomerase has been identified in many cultured cell lines and actively dividing cell types. The active

reverse transcriptase component has been identified in teh TERT protein. The presence of this factor determines

the availability of the telomerase function. The TERT protein has a high turnover rate and its expression is

regulated by factors that promote growth (c-MYC, v-k-ras, Bcl-2 and E6) and inhibiting factors (RB and p53)

that promote cell death or that block cell division. It appears that the regulation of active telomerase has many

levels and can be inhibited by TEP1 not releasing TERT or by TRF1 which binds the end repeats and prevents

access to the chromosome ends. Additional modulation is due to phosphorlyation by PKC and AKT or

dephophorylation by PP2A.

Wilke et al found that a case of human alpha-thalassemia was caused by a truncation of

chromosome 16 that had been healed by the addition of telomeric repeats (TTAGGG)n.

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Human telomeres consist of many kilobases of (TTAGGG)n together with various

associated proteins. Small amounts of these terminal sequences are lost from the tips of

the chromosomes during each S phase because of incomplete DNA replication, but de novo

addition of TTAGGG repeats by the enzyme telomerase compensates for this loss. Many

human cells progressively lose terminal bases with each cell division, a loss that correlates

with the apparent absence of telomerase in these cells. There has been considerable

interest in the possible relationship between human telomeres and cellular senescence and

immortalization. This interest includes the question of a role in the malignant process and

the question of the use of telomerase inhibitors as anti-tumor drugs.

TACI

和

BCMA< /p>

调节

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细胞免疫

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TACI and BCMA signal transduction pathway that enhances cell survival APRIL and BAFF (also called TALL-I and

BLyS) are TNF family members that act as ligands for the BCMA and TACI receptors. Both APRIL and BAFF bind

to both the BCMA and TACI receptors to activate the humoral immune response, stimulating B cell

immunoglobulin production and proliferation. BAFF is found as a membrane bound form in T cells and a soluble

form that is released from the cell to stimulate B cell proliferation and differentiation. As members of the TNF

receptor gene family, BCMA and TACI interact with TRAF family members to transduce signals downstream to

NF- kappaB activation and MAP kinase pathways. Abnormally active BAFF or APRIL signaling may play a role in

autoimmune disorders such as lupus.

T

辅助细胞的表面受体

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T

细胞受体信号通路

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