CST公司信号通路图Growth & Differ
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.
干货细胞信号通路图解之干细胞发育分化相关信号通路
干货细胞信号通路图解之干细胞发育分化相关信号通路（1）Wnt / β-Catenin Signaling：保守的Wnt/β-Catenin信号通路可以调节发育中干细胞的多能性和细胞命运的决定过程。
在发育过程中的许多不同的细胞和组织里，Wnt/β-catenin整合许多其他通路所传递的信号，如视黄酸，FGF，TGF-β和BMP。
Wnt配体(Wnt-ligand)是一个分泌的糖蛋白，它和Frizzled受体结合，引起信号的级联反应，最后导致多功能激酶GSK-3β从APC/Axin/GSK-3β复合体中被释放出来。
在没有Wnt信号刺激时(关闭状态),β-catenin，既是一个完整的细胞-细胞粘附接头蛋白也是一个转录调节辅因子，被APC/Axin/GSK-3β复合体标记而降解。
CK1和GSK-3β协同对β-catenin磷酸化使它通过β-TrCP/SKP被泛素化和蛋白酶体降解。
当Wnt结合后(开启状态)，共受体LRP5/6和与Wnt结合的Frizzled被带进了复合体内，这导致Dishevelled (Dvl)被依次磷酸化，泛素化和多聚化从而被激活，这就取代了APC/Axin中的GSK-3β,其中的机制不清楚，有可能是通过捕获底物和/或内涵体封存。
Wnt配体的转录效应是由β-catenin依赖Rac1的核转运并结合到LEF/TCF DNA结合因子上来介导的，在其中充当转录的共激活因子，通过代替Groucho-HDAC共抑制因子发挥部分作用。
另外，与同结构域因子Prop-1形成复合体后，β-catenin已被发现存在于条件依赖的活化和抑制复合体中。
重要的是，在一些癌症中发现β-catenin存在点突变使它阻止GSK-3β的磷酸化从而导致异常的累积。
还有E-cadherin，APC和axin的突变在肿瘤样品中也有记录，这说明这条通路非正常的激活与癌症有关。
除此之外，通路中的GSK-3β还参与糖原代谢和其他的关键通路，所以它的抑制与糖尿病和神经退行性疾病相关。
信号转导.2010
PI3K
Grb2 Sos
PLC PIP2
DAG PKC Ca2+ IP3
靶蛋白
Ras Raf MEK
磷酸化
靶蛋白 磷酸化
ERK
转录因子 磷酸化
靶基因 转录
CST途径
激素 等 生长 因子 细胞 因子 甾体 激素 G 蛋 白 TPK cAMP AC PLC IP3 -Ca2+ DG PKA
CaM.PK
PKC
生理 效应
Ras
MAPK
TF
P
(非受体TPK) JAK
不同通路间存在
交互通话（cross-talk）
胞浆受体
核受体介导的 信 号 转 导通路
DNA结合区 激素结合区 雌激素与DNA结合 模式图
配体依赖的转录调节因子 配体主要为激素类的脂溶性分子
细胞信号转到通路调节靶蛋白活性的 主要方式
可逆的磷酸化快速调节效应蛋白的活性
集合管腔
H2O
H2O
ATP
H2O
受体或受体后信号转导异常
受体异常与疾病 •遗传性受体病
•自身免疫性受体病
抗自身受体的抗体 重症肌无力等 ①刺激型受体抗体 自身免疫性甲状腺病 ②抑制型受体抗体
自身免疫性受体病 o 自身免疫性的甲状腺病(P103)
甲状 Ras Raf ERK TSHR 腺素 PLC DG PKC 桥本病
eg)
MAPK family
stimuli Growth factors Cytokines Cellular stress
Mitogen activated protein kinase
ATP MAPKKK
MAPபைடு நூலகம்K
RCST_Install_Guide-a
重要警告:
注意下面的预防措施用来防止破坏RCST或它的电源。
RXIFL电缆与RCST和LNB连接好之前，不得开启RCST电源！
如果RCST背面RX IN接头的中心脚对地短路，将烧坏RCST的印刷电路板，使该RCST无法运行。
RX同步建立之前，不得连接TXIFL电缆到BUC！
如果到BUC的发射电缆错误的连接到RCST RX IN接头,过多的电流将立即冲击设备，可能会损坏RCST电源。
鱼鳞式包装带（Fish tape）,100英尺
拖绳，1/2英寸，200英尺，聚酯材料。
电缆拖拉把手，直径0.37-0.49英寸电缆用
管道扳手，18英寸
测试设备
模拟或数字伏特-欧姆表
2路分配器/1路直流通过
转接头：
F阴转N阳
F阴转BNC阳
BNC阴转N阳
两根3英尺测试用同轴电缆，RG6阳/阳
频谱分析仪950-1750兆赫或峰值测量仪
例：
MAC=OE.00.01.01.72.bd
缺省的IP=10.0.114.189
这里72（hex）=114(dec)并且bd(hex)=189(dec)
网络IP地址
NOC提供或作为远程站安装资料清单的一部分。
表6IP地址
缺省的IP地址只有在RCST成为请求传输状态之前是有效的。一旦RCST成为TX同步，它就从RNCC接收它的网络IP地址同时缺省的IP地址不再有效。要重新建立缺省的IP地址，必须断开该终端背面的TX/RX电缆，这样，它就会自动复位为缺省的IP地址。
100 - 200英尺
RG-6类型
F头
Yes
RG-8类型
N头
No
200-400英尺
病理生理——细胞信号转导与疾病
•基因突变：遗传病或肿瘤 •配体异常 •病理性刺激
☆霍乱 霍乱毒素致G蛋白异常
(cholera toxin, CT)
42
☆霍乱
机制
肠腔
H2O Cl-
Na+
cAMP ↑ ↑ ↑
CT Gs
AC
ATP
表现：剧烈呕吐腹泻，严重脱水，休克
43
2
❖CST系统概述
➢ 细胞信号转导系统
(cell signaling system)
---能接受信号的受体 ---受体后信号转导通路 ---信号转导通路作用的靶蛋白
3
❖CST系统概述
➢ 细胞信号转导
(cell signal transduction, CST)
---胞外信息分子通过作用于胞膜或胞 内受体，经细胞内信号转导通路的转 换而影响细胞生物学功能的过程
◆ G蛋白耦联受体 ◆ 酪氨酸蛋白激酶受体 ◆ 与酪氨酸蛋白激酶连接的受体 ◆ 丝/苏氨酸蛋白激酶受体 ◆ 肿瘤坏死因子受体家族 ◆ 离子通道受体
核受体介导的信号转导通路
13
G蛋白耦联受体介导的信号转导通路
◆ G蛋白耦联受体
(G protein coupled receptor, GPCR)
—为七次跨膜受体
核受体介导的信号转导通路
Cortisol
HSP R HSP
R HSP
RR
HSP
RR Gene
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❖CST通路
➢CST的主要通路 ➢CST通路靶蛋白活性调节方式
☆通过可逆磷酸化快速调节 ☆通过调控基因表达产生较为缓慢
的生物效应
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信号通路研究cell signal pathways
信号通路研究cell signal pathways Cell Signaling Technology, Inc (CST) 是美国著名的生物公司和细胞信号转导研究的领袖，提供特色的信号转导检测用抗体及磷酸化抗体、ELISA试剂盒、激酶等产品。
CST总部位于美国波士顿，毗邻哈佛、麻省理工等著名学府的雄厚人才资源，拥有专业的生产和研发队伍，发表的文章多次收录在Nature, Cell, Journal of Immunology等杂志上。
其高质量的产品和专业的研发精神已被全球客户推崇为“细胞信号转导研究的金标准”！点击下面的图标可以看信号通路大图：Chromatin Regulation / Acetylation∙Protein Acetylation∙Histone MethylationMitogen-Activated Protein Kinase (MAPK) Cascades∙Mitogen-Activated Protein Kinase Cascades∙MAPK/Erk in Growth and Differentiation∙G-Protein-Coupled Receptors Signaling to MAPK/Erk∙SAPK/JNK Signaling Cascades∙p38 MAPK Signaling Pathways Apoptosis / Autophagy∙Overview: Regulation of Apoptosis∙Inhibition of Apoptosis∙Death Receptor Signaling∙Mitochondrial Control of Apoptosis∙Autophagy SignalingPI3K / Akt Signaling Translational Control∙Regulation of eIF4E and p70 S6 Kinase ∙Regulation of eIF2∙mTor SignalingCa, cAMP & Lipid Signaling∙Protein Kinase C Signaling∙Phospholipase SignalingCell Cycle and Checkpoint Control∙G1/S Checkpoint∙G2M/DNA Damage CheckpointDNA DamageJak/Stat Pathway∙IL-6 Receptor SignalingNF-κB Signaling∙NF-κB Signaling∙Toll-Like Receptor SignalingTGF-β SignalingNeuroscience∙Amyloid Plaque and Neurofibrillary Tangle Formation in Alzheimer's Disease∙Dopamine Signaling in Parkinson's Disease Lymphocyte Signaling∙ B Cell Receptor Signaling∙T Cell Receptor SignalingTyrosine Kinase/ Adaptors∙Receptor & Cytoplasmic Tyrosine Kinases∙ErbB / HER Signaling∙Adaptor ProteinsAngiogenesisVesicle TraffickingCytoskeletal Signaling∙Regulation of Microtubule Dynamics∙Regulation of Actin DynamicsAdhesion∙Adherens Junction DynamicsEmbryonic Stem Cell and Lineage MarkersGlucose Metabolism∙Insulin Receptor Signaling∙AMPK SignalingWnt / Hedgehog / Notch∙Wnt / β-Catenin Signaling∙Hedgehog Signaling in Vertebrates∙Notch SignalingNuclear Receptor更多产品信息请联系：广州聚研生物科技有限公司电话：86-20-87322722/ 87328692传真：86-20-87328692网址：/地址：广州市中山一路51号拓业大厦506室（510600）E-mail：info@。
Signal Transduction and the Related Disorders(7)
心输出量↓
儿茶酚胺 心肌收缩力↑
ATⅡ
醛固酮 -化学刺激 加压素 内皮素
回心血量↑
（一）参与心肌肥厚的信号转导通路 1. 激活PLC-PKC途径 2. 激活cAMP-PKA途径 3. 激活MAPK家族的信号通路
4. 其他一些信号通路
（二）与心力衰竭发生相关的信号转导异常
1. β肾上腺素信号转导继发性异常
2. 调控基因表达的缓慢效应
细胞信号转导异常
1. 疾病的直接原因, 导致疾病的发生 2. 作用于疾病进展过程, 促进疾病的发展 3. 决定疾病的严重程度及药物的敏感性 4. 单一或多环节, 甚至多条信号转导通路异常
细胞外信号发放异常
1. 体内神经或体液因子分泌异常增多或减少
胰岛素不足/抗胰岛素抗体→糖尿病 生长素过少→侏儒症 脑缺血、缺氧/创伤→谷氨酸↑→受体过度激活
TSA B TSH R
Gs Gq
Gs-Ac-cAMP
Gq-PLC-DAG-PKC
T4↑↑
B. 阻断型抗体 桥本病、重症肌无力
受体异常
3.继发性受体异常 上调或增敏 后者指结构或调节功能变化，使靶细 下调或减敏 胞对配体的刺激反应过度或减弱。
前者指数量上的增减
受体后的信号转导通路成分异常
霍乱 霍乱毒素
细胞信号转导通路调节靶蛋白的方式
1.可逆磷酸化的快速调节：蛋白激酶、磷酸酶
受体磷酸化-去磷酸化是调节受
体亲和力与活性的重要方式
PKA
Ca2+通道 磷酸化
心肌Ca2+转运↑
心肌 收缩↑
促进CRE的结合，激活靶基因转录
刺激
↓
MAPKKK
生长因子 丝裂原,GPCR ↓
CST公司产品及市场分析
Green Red Colorless Colorless Colorless Yellowish Blue
7216S组分 4E-BP1 (T37/46) Ab Coated Microwells 4E-BP1 Detection Ab Anti-mouse IgG, HRPlinked Antibody TMB Substrate #7004 STOP Solution #7002 Sealing Tape ELISA Wash Buffer (20X) Cell Lysis Buffer (10X) #9803 ELISA Sample Diluent
名称
PathScan® Total 4E-BP1 Sandwich ELISA Kit PathScan® Phospho-4E-BP1 (Thr37/Thr46) Sandwich ELISA Kit
溶液颜色
规格
1 Kit ( 96 assays ) 1 Kit ( 96 assays )
反应种属
组分 体积 溶液颜色 管帽颜色 Phospho-p44/42 MAPK (Thr202/Tyr204) Rabbit Antibody Coated 16 tests Microwells p44/42 MAPK Mouse Detection Antibody Anti-Mouse IgG HRP-Linked Antibody p38α MAPK (T180/Y182) Mouse Ab Coated Microwells Phospho-p38α MAPK (Thr180/Tyr182) Rabbit Detection Ab Anti-Rabbit IgG HRP-Linked Ab MEK1 Mouse Ab Coated Microwells MEK1 Rabbit Detection Ab Anti-Rabbit IgG HRP-Linked Ab MEK1 Mouse Ab Coated Microwells Phospho-MEK1/2 (Ser217/221) Rabbit Detection Ab Anti-Rabbit IgG HRP-Linked Ab SAPK/JNK Mouse Antibody Coated Microwells SAPK/JNK Rabbit Detection Ab Anti-Rabbit IgG HRP-Linked Ab SAPK/JNK Mouse Antibody Coated Microwells Phospho-SAPK/JNK (Thr183/Tyr185) Rabbit Detection Antibody Anti-rabbit IgG HRP-Linked Antibody TMB Substrate STOP Solution Sealing Tape 20X Wash Buffer Sample Diluent Cell Lysis Buffer (10X) #9803 1.8 ml 1.8 ml 16 tests 1.8 ml 1.8 ml 16 tests 1.8 ml 1.8 ml 16 tests 1.8 ml 1.8 ml 16 sheets 1.8 ml 1.8 ml 16 tests 1.8 ml 1.8 ml 11 ml 11 ml 2 sheets 25 ml 25 ml 15 ml Colorless Blue Yellowish Green Red Colorless Colorless Purple Purple Green Red Gray Gray Green Red Green Green Green Red White White Green Red Yellow Yellow Green Red Light Pink Light Pink