Wnt 信号通路图
Wnt信号通路在成骨细胞中的作用：成骨还是破骨？
中国组织工程研究 第18卷 第33期 2014–08–13出版Chinese Journal of Tissue Engineering Research August 13, 2014 Vol.18, No.33P .O. Box 10002, Shenyang 110180 5366www.CRTER .org刘艳玲，女，1983年生，四川省三台县人，汉族，泸州医学院口腔医学院在读硕士，医师。
doi:10.3969/j.issn.2095-4344. 2014.33.021 []中图分类号:R318 文献标识码:A 文章编号:2095-4344 (2014)33-05366-06 稿件接受：2014-07-08Liu Yan-ling, Studying for master’s degree, Physician, Stomatological Hospital of Luzhou Medical College, Luzhou 646000, Sichuan Province, China; Department of Stomatology, People’s Hospital of Deyang, Deyang 618000, Sichuan Province, ChinaAccepted: 2014-07-08Wnt 信号通路在成骨细胞中的作用：成骨还是破骨？刘艳玲1，2，李方兵2，赵 曦2 (1泸州医学院口腔医学院，四川省泸州市 646000；2德阳市人民医院口腔科，四川省德阳市 618000)文章亮点：1 此问题的已知信息：研究表明，Wnt 信号通路参与调节骨髓间充质干细胞向成骨细胞分化，促进成骨细胞增殖和分化，抑制成骨细胞的程序性死亡，间接影响破骨细胞的功能。
2 文章增加的新信息：Wnt 信号途径是体内重要的信号调节系统之一，对成骨细胞、破骨细胞和软骨细胞的分化、增殖和程序性死亡过程中扮演重要角色。
WNT信号通路
APC(adenomatous polyposis coli)是一种与结肠癌 发生有关的抑癌基因。定位于5q21，长度10.4kb， 编码一组较大的多结构域蛋白，属于胞浆蛋白，具 有支架蛋白的作用。APC蛋白、Axin和GSK3,可与 β-catenin形成复合物，而促进β-catenin发生磷酸化， 使β-catenin得以被蛋白酶降解。在固有的和散在的 大多数结直肠肿瘤中，均已发现有APC基因的突变 或缺失。APC基因突变可发生于任何外显子，其中 以第15外显子（654-2843密码子）最为常见 ［2000］，1020-1169密码子和1323-2075密码子编 码区域被认为是β-catenin与APC的结合位点，该区 域突变即导致β-catenin不能与APC结合，进而不能 被GSK3磷酸化，以致β-catenin降解受阻而积聚于胞 浆。因而APC是Wnt途径的负调控因子。在其他癌 症如髓母细胞瘤，侵袭性纤维瘤病，乳腺癌等也可 见APC异常。
Axin具有多个蛋白-蛋白作用域，与APC一样起支 架蛋白的作用，是支架蛋白复合体的构建基础。 Axin的RGS功能域(regulators of G protein signaling domain)，能与全长的APC结合，但不能与截短的无 活性APC结合。APC-Axin-GSK-β-catenin形成复合 物时，GSK靠近β-catenin而促使其磷酸化，因此也 是Wnt途径的负调控因子。在肝癌、结直肠癌、乳 腺癌等肿瘤中检测到Axin基因突变，目前Axin被认 为是抑癌分子，其基因突变可促进肿瘤的发生。
TCF是Wnt途径下游组分，属于DNA结合 蛋白，包括1个HMG盒子(highmobility group) 和β-catenin作用域。HMG盒子具有与DNA结合 的活性，通过与其它因子发生作用，而激活 转录活性。有趣的是，TCF转录因子家族的 不同成员具有不同的特性。尽管它们都可结 合DNA，但在大部分情况下并不能激活转录， 只有与β-catenin发生作用后，才可激活转录 过程。有报道在结直肠癌中，检测出Tcf-4突 变，且同时存在APC或β-catenin的突变，推测 Tcf-4突变可能是附加突变。
Wnt信号通路调控机理
核内的调控
β-catenin的N端可以与Bc19结合，Bc19是一类特异性参
与β-catenin转录的辅因子。
Bc19包括HD1和HD2两个功能区域。
HD2区域与β-catenin结合，HD1区域与Pygo的PHD区域
结合，将β-catenin与Pygo联接起来。Pygo由NHD与PHD 两个区域构成。Pygo的PHD区域可以结合H3K4甲基化的 染色质，促进β-catenin在WRE和转录活性位点的结合。
β-catenin蛋白三个功能区域
N端ຫໍສະໝຸດ 可以结合辅因子Bc19.
中段和C端：由12个Armadillo重复区段（R1~R12）组成
R3~R10区域介导了β-catenin与TCF的结合，此区域的缺
失会使β-catenin对下游基因的激活作用完全丧失。
C端区域为转录激活区域，可以结合一系列通用转录辅因 子如染色质重塑因子，组蛋白乙酰转移酶，促进转录的起 始和延伸。
Wnt下游基因的反馈调控
Wnt信号通路的生物学效应最终是通过控制 其目标基因的表达实现的。 Wnt信号在不同的组织和发育阶段引起的效 应各不相同，但大部分Wnt信号通路的调控 因子的表达都受Wnt通路自身所调控。
thanks
Wnt基因及其蛋白
Wnt蛋白
修饰主要有两种:糖基化和棕榈酰化
属于一类高度不溶的蛋白，这主要是因为
其脂质化修饰。
Wnt三条信号通路
经典Wnt通路(Wnt/β-catenin通路) Wnt/PCP通路( planar cell polarity pathway)
Wnt/钙离子(Wnt/Ca2+)通路
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 )
Wnt信号通路与肝纤维化的关系
3Ｗｎｔ信号通路与肝纤维化的关系范 钦１，李红俊２，李晓霞２，杨 尹２，陈海燕２，成家茂１１大理大学基础医学院解剖学教研室，云南大理６７１０００；２大理大学临床医学院超声教研室，云南省第四人民医院超声科，云南大理６７１０００摘要：在各种慢性肝损伤后，肝纤维化是生物体的一种自我修复性病理过程，并能引起肝硬化、肝癌等疾病。
Ｗｎｔ信号通路广泛存在于无脊椎动物和脊椎动物中，是一类在物种进化过程中高度保守的信号通路。
许多研究已经证实Ｗｎｔ信号通路与肝纤维化的发生发展有密切联系。
主要从经典和非经典Ｗｎｔ信号通路调控肝星状细胞、肝巨噬细胞、肝祖细胞的机制方面进行概述，为后续深入开展Ｗｎｔ信号调控肝纤维化机制研究及探索可逆转肝纤维化的治疗靶点提供新思路。
关键词：肝硬化；Ｗｎｔ信号通路；肝星状细胞；枯否细胞；干细胞基金项目：２０２１年云南省地方本科高校基础研究联合专项资金面上项目（２０２１０１ＢＡ０７０００１－１０１）；２０２２年云南省教育厅科学研究基金（２０２２Ｙ８０９）；２０２１年云南省教育厅科学研究基金（２０２１Ｊ０３８２）；２０１７年度云南省自然科学基金高校联合基金（２０１７ＦＨ００１－０７６）；云南省李云庆专家工作站项目（２０２００５ＡＦ１５００１４）；大理大学神经生物学创新团队项目（ＺＫＬＸ２０１９１０８）ＡｓｓｏｃｉａｔｉｏｎｂｅｔｗｅｅｎｔｈｅＷｎｔｓｉｇｎａｌｉｎｇｐａｔｈｗａｙａｎｄｈｅｐａｔｉｃｆｉｂｒｏｓｉｓＦＡＮＱｉｎ１，ＬＩＨｏｎｇｊｕｎ２，ＬＩＸｉａｏｘｉａ２，ＹＡＮＧＹｉｎ２，ＣＨＥＮＨａｉｙａｎ２，ＣＨＥＮＧＪｉａｍａｏ１．（１．ＤｅｐａｒｔｍｅｎｔｏｆＨｕｍａｎＡｎａｔｏｍｙ，ＢａｓｉｃＭｅｄｉｃａｌＣｏｌｌｅｇｅｏｆＤａｌｉＵｎｉｖｅｒｓｉｔｙ，Ｄａｌｉ，Ｙｕｎｎａｎ６７１０００，Ｃｈｉｎａ；２．ＤｅｐａｒｔｍｅｎｔｏｆＵｌｔｒａｓｏｕｎｄ，ＳｃｈｏｏｌｏｆＣｌｉｎｉｃａｌＭｅｄｉｃｉｎｅ，ＤａｌｉＵｎｉｖｅｒｓｉｔｙ；Ｄｅ ｐａｒｔｍｅｎｔｏｆＵｌｔｒａｓｏｕｎｄ，ＴｈｅＦｏｕｒｔｈＰｅｏｐｌｅ’ｓＨｏｓｐｉｔａｌｏｆＹｕｎｎａｎＰｒｏｖｉｎｃｅ，Ｄａｌｉ，Ｙｕｎｎａｎ６７１０００，Ｃｈｉｎａ）Ｃｏｒｒｅｓｐｏｎｄｉｎｇａｕｔｈｏｒｓ：ＣＨＥＮＧＪｉａｍａｏ，ｃｈｊｍａｏ＠１６３．ｃｏｍ；ＣＨＥＮＨａｉｙａｎ，３１６５７３２３０＠ｑｑ．ｃｏｍＡｂｓｔｒａｃｔ：Ｈｅｐａｔｉｃｆｉｂｒｏｓｉｓ（ＨＦ）ｉｓａｓｅｌｆ－ｈｅａｌｉｎｇｐａｔｈｏｌｏｇｉｃａｌｐｒｏｃｅｓｓａｆｔｅｒａｌｌｋｉｎｄｓｏｆｃｈｒｏｎｉｃｌｉｖｅｒｉｎｊｕｒｉｅｓａｎｄｃａｎｃａｕｓｅｄｉｓｅａｓｅｓｓｕｃｈａｓｌｉｖｅｒｃｉｒｒｈｏｓｉｓａｎｄｌｉｖｅｒｃａｎｃｅｒ．ＴｈｅＷｎｔｓｉｇｎａｌｉｎｇｐａｔｈｗａｙｉｓｈｉｇｈｌｙｃｏｎｓｅｒｖｅｄｉｎｓｐｅｃｉｅｓｅｖｏｌｕｔｉｏｎａｎｄｗｉｄｅｌｙｅｘｉｓｔｓｉｎｉｎｖｅｒｔｅｂｒａｔｅｓａｎｄｖｅｒｔｅｂｒａｔｅｓ，ａｎｄｍａｎｙｓｔｕｄｉｅｓｈａｖｅｃｏｎｆｉｒｍｅｄｔｈａｔｔｈｅＷｎｔｓｉｇｎａｌｉｎｇｐａｔｈｗａｙｉｓｃｌｏｓｅｌｙａｓｓｏｃｉａｔｅｄｗｉｔｈｔｈｅｄｅｖｅｌｏｐｍｅｎｔａｎｄｐｒｏｇｒｅｓｓｉｏｎｏｆＨＦ．Ｔｈｉｓａｒｔｉｃｌｅｒｅｖｉｅｗｓｔｈｅｍｅｃｈａｎｉｓｍｓｏｆｔｈｅｃｌａｓｓｉｃａｌａｎｄｎｏｎ－ｃｌａｓｓｉｃａｌＷｎｔｓｉｇｎａｌｉｎｇｐａｔｈｗａｙｓｉｎｒｅｇｕｌａｔｉｎｇｈｅｐａｔｉｃｓｔｅｌｌａｔｅｃｅｌｌｓ，ｈｅ ｐａｔｉｃｍａｃｒｏｐｈａｇｅｓ，ａｎｄｈｅｐａｔｉｃｐｒｏｇｅｎｉｔｏｒｃｅｌｌｓ，ｓｏａｓｔｏｐｒｏｖｉｄｅｎｅｗｉｄｅａｓｆｏｒｓｕｂｓｅｑｕｅｎｔｓｔｕｄｉｅｓｏｎｔｈｅｍｅｃｈａｎｉｓｍｏｆｔｈｅＷｎｔｓｉｇｎａｌｉｎｇｐａｔｈｗａｙｉｎｒｅｇｕｌａｔｉｎｇＨＦａｎｄｆｕｒｔｈｅｒｅｘｐｌｏｒａｔｉｏｎｏｆｔｈｅｒａｐｅｕｔｉｃｔａｒｇｅｔｓｔｈａｔｃａｎｒｅｖｅｒｓｅＨＦ．Ｋｅｙｗｏｒｄｓ：ＬｉｖｅｒＣｉｒｒｈｏｓｉｓ；ＷｎｔＳｉｇｎａｌｉｎｇＰａｔｈｗａｙ；ＨｅｐａｔｉｃＳｔｅｌｌａｔｅＣｅｌｌｓ；ＫｕｐｆｆｅｒＣｅｌｌｓ；ＳｔｅｍＣｅｌｌｓＲｅｓｅａｒｃｈｆｕｎｄｉｎｇ：ＧｅｎｅｒａｌＰｒｏｊｅｃｔｏｆＳｐｅｃｉａｌＪｏｉｎｔＦｕｎｄｆｏｒｔｈｅＢａｓｉｃＲｅｓｅａｒｃｈｏｆＬｏｃａｌＵｎｄｅｒｇｒａｄｕａｔｅＣｏｌｌｅｇｅｓａｎｄＵｎｉｖｅｒｓｉｔｉｅｓｉｎＹｕｎｎａｎＰｒｏｖｉｎｃｅｉｎ２０２１（２０２１０１ＢＡ０７０００１－１０１）；Ｔｈｅ２０２２ＳｃｉｅｎｔｉｆｉｃＲｅｓｅａｒｃｈＦｕｎｄｏｆｔｈｅＥｄｕｃａｔｉｏｎＤｅｐａｒｔｍｅｎｔｏｆＹｕｎｎａｎＰｒｏｖｉｎｃｅ（２０２２Ｙ８０９）；Ｔｈｅ２０２１ＳｃｉｅｎｔｉｆｉｃＲｅｓｅａｒｃｈＦｕｎｄｏｆｔｈｅＥｄｕｃａｔｉｏｎＤｅｐａｒｔｍｅｎｔｏｆＹｕｎｎａｎＰｒｏｖｉｎｃｅ（２０２１Ｊ０３８２）；Ｔｈｅ２０１７ＪｏｉｎｔＵｎｉｖｅｒｓｉ ｔｙＦｕｎｄｏｆＮａｔｕｒａｌＳｃｉｅｎｃｅＦｏｕｎｄａｔｉｏｎｏｆＹｕｎｎａｎＰｒｏｖｉｎｃｅ（２０１７ＦＨ００１－０７６）；ＰｒｏｊｅｃｔｏｆＬｉＹｕｎｑｉｎｇＥｘｐｅｒｔＷｏｒｋｓｔａｔｉｏｎｏｆＹｕｎｎａｎＰｒｏｖ ｉｎｃｅ（２０２００５ＡＦ１５００１４）；ＩｎｎｏｖａｔｉｏｎＴｅａｍｏｆＮｅｕｒｏｂｉｏｌｏｇｙｏｆＤａｌｉＵｎｉｖｅｒｓｉｔｙ（ＺＫＬＸ２０１９１０８）ＤＯＩ：１０．３９６９／ｊ．ｉｓｓｎ．１００１－５２５６．２０２２．０２．０３８收稿日期：２０２１－０７－０５；录用日期：２０２１－０８－１１通信作者：成家茂，ｃｈｊｍａｏ＠１６３．ｃｏｍ；陈海燕，３１６５７３２３０＠ｑｑ．ｃｏｍ 肝纤维化是慢性肝损伤后进一步恶化的关键性病理过程，是提升肝癌风险的关键因素，目前尚无特异有效的治疗方法。
Wnt信号通路
• Nearly 50% of cellular protein is found in the cytosolic fraction. As commonly observed for subcellular fractionations of other mammalian cells [22], the plasma membraneenriched fraction displayed ~30% and nuclear-enriched fraction 12-13% of the cellular protein. The sum of mitochondria-enriched fraction and of high-speed, supernatant “microsomal” fraction, together representing ~10% of the cellular protein and essentially devoid of markers for plasma membrane, cytoplasm, or nucleus, were not further probed in these studies. The amount of the marker proteins and signaling elements established empirically in the plasma membrane + cytoplasm + mitochondria + microsomes + nuclear-enriched fractions was set to 100% for all derivative calculations of signaling element distribution (Table 1).
Wnt信号通路调控
ProteinkinaseC), 从而引起细胞内Ca2+浓度增加
和Ca2+敏感信号成分的激活, 以调节细胞运动和
细胞粘着性。
该通路能拮抗经典的Wnt通路
经典Wnt通路及其调控
经典Wnt通路,该通路激活后导致细胞质内 β-catenin的稳定和积累, 然后β-catenin进入 细胞核内激活靶基因表达； WNT信号通路由以下部分组成：细胞外的 WNT配体蛋白、细胞膜上的受体、细胞浆 内的信号传导部分和核内的转录调控部分 。
β-catenin蛋白三个功能区域
N端
可以结合辅因子Bc19.
中段和C端：由12个Armadillo重复区段（R1~R12）组成
R3~R10区域介导了β-catenin与TCF的结合，此区域的缺
失会使β-catenin对下游基因的激活作用完全丧失。
C端区域为转录激活区域，可以结合一系列通用转录辅因 子如染色质重塑因子，组蛋白乙酰转移酶，促进转录的起 始和延伸。
经典Wnt通路调控机理
胞浆内的调控 核内的调控 Wnt下游基因的反馈调控
胞浆内的调控
经典的Wnt信号通路中，对β-catenin浓度的调控 处于中心地位。βcatenin的浓度受Axin/GSK3/APC复合体控制
Axin/GSK-3/APC复合体：Axin蛋白结合GSK3、 CK1、β-catenin形成
胞浆内的调控
Wnt受体由Fz和LRP5/6组成。 Wnt蛋白与受体的结合引起LRP5/6的磷酸化和Fz-LRP5/6 复合体的形成。Dsh可以与Fz结合，LRP5/6含有5个连续 的PPPSPXS区域， Axin可以与磷酸化的PPPSPXS结合，同时Axin结合 GSK3、CK1,引起GSK3、CK1对其余PPPSPXS区域的磷 酸化，PPPSPXS的磷酸化又进一步促进Axin的结合。 Dsh和Axin都含有一个DIX结构域，二者可以通过这一区 域形成Dsh-Dsh或Dsh-Axin多聚体，促进Wnt-Fz-LRP5/6 复合物的形成。 Axin蛋白与LRP5/6的结合导致了Axin复合物的解体，从 而促进β-catenin的稳定性
Wnt信号通路
β-catenin降解障碍 胞浆内游离的β-catenin聚集 激活下游靶细胞CyclinD1、C-myc等基因转录
肿瘤发生
Wnt信号通路与人类疾病
2.糖尿病
胰岛素与其受体结合 GSK-3失活
（glycogen synthase kinase 3 ）
激活葡萄糖合酶
合成糖原及相与人类疾病
Ⅱ. 黑素干细胞Wnt信号通路的失活可导 致脱色素，头发即呈现出灰色。
Ⅲ. 头发毛囊干细胞中的异常Wnt信号会 阻止头发的再生。
10 June 2011
Wnt信号通路与人类疾病
1.癌症
APC基因突变
β-catenin基因突变
β-catenin降解复合物合成障碍
β-catenin无法被磷酸化和泛素化降解
3.心脑血管疾病
LRP
（low density lipo-protein receptor related protein）
Cys
Arg
Wnt信号受损 冠心病
Thank you！
功能
1、参与胚胎发育
胚胎形成
促进体节形成 促进体轴形成 抑制头形成
组织器官发生 脑、心脏、肺……
生殖系统发生 Wnt-4抑制雄激素合成
功能
2、参与干细胞的更新和分化
Brain Area-Specific Effect of TGF-β Signaling on Wnt-Dependent Neural Stem Cell Expansion
2、参与干细胞的更新和分化
Coordinated Activation of Wnt in Epithelial and Melanocyte Stem Cells Initiates
Wnt信号通路
Wnt信号通路有关成骨细胞(OB)的研究,侧重于Wnt信号通路及相关节点的特征及功能。
Wnt 是一组可分泌的蛋白家族,体内许多器官和组织都能分泌Wnt。
成骨细胞分泌的Wnt 通过自分泌和旁分泌对骨发育和骨量维持起重要作用。
因而,通过Wnt信号通路研究,可能找到而且已经找到新的促成骨药物(如Sclerostin抗体)。
Wnt分子迄今被发现有多种形式(Wnt-1到Wnt5a),其受体为1个7次跨膜大分子(发卷样蛋白),低密度脂蛋白受体相关蛋白5和6(LRP5/6)是Wnt共同受体。
Wnt 与受体/共同受体结合后的信号通路极其复杂,可分为经典途径[通过Wnt/β-catenin(β-连环蛋白)]和非经典胞内途径(Wnt/Ca2+和Wnt/ 平面细胞极化PCP)。
基因对骨代谢的影响有学者报告,将LRP6基因在成骨细胞中条件性敲除,小鼠骨量明显减少,伴成骨功能降低和骨吸收增加,首次证明了LRP6对骨代谢的调节作用。
LRP5突变依突变位点位置不同,既可以减少骨量又可以增加骨量,库伊(Cui)等将G171V和A214V突变引入小鼠体内成骨细胞,观察到小鼠皮质骨和松质骨骨量增加,证明人体的LRP5之G171V突变伴随的高骨量是由成骨细胞自身造成,不一定是全身系统性作用。
跨膜蛋白Kremen可与LRP5/6结合,其在骨中的功能尚不清楚。
Saito等将Kremen1或Kremen2基因分别敲除未见到小鼠骨量变化,这两种基因同时被敲除才显示骨量增加,说明这两个亚单位功能基本上可以互相代偿,该复合体的生理功能是抑制Wnt/β-catenin信号通路。
舒尔策(Schulze)等建立的成骨细胞过度表达Kremen2小鼠模型显示骨量极度减少,骨形成速度极度减慢伴破骨细胞数目显著增加,进一步肯定了该复合体的功能。
重组人甲状旁腺激素(PTH)已用于临床治疗骨质疏松,但其机制尚不清楚。
旺(Wan)等报告,PTH促成骨的机制之一,是促进体内OB中β-连环蛋白的表达,但该作用不是通过Wnt,而是通过PTH1R与LRP5/6结合,促进LRP5/6磷酸化而导致的。
Wnt信号通路
Wnt信号途径2008-06-05 10:57Wnt是一类分泌型糖蛋白，通过自分泌或旁分泌发挥作用。
在小鼠中，肿瘤病毒整合在Wnt之后而导致乳腺癌，命名为Int1，它与果蝇的无翅基因（Wingless，wg）有高度同源性。
Wnt信号途径能引起胞内β-连锁蛋白（β-catenin）积累。
β-catenin（在果蝇中叫做犰狳蛋白Armadillo）是一种多功能的蛋白质，在细胞连接处它与钙粘素相互作用，参与形成粘合带，而游离的β-catenin可进入细胞核，调节基因表达。
Wnt信号在动物发育中起重要作用，其异常表达或激活能引起肿瘤。
Wnt的受体是卷曲蛋白（frizzled，Frz），为7次跨膜蛋白，结构类似于G蛋白偶联型受体，Frz胞外N端具有富含半胱氨酸的结构域（cysteine rich domain，CRD），能与Wnt结合。
Frz作用于胞质内的蓬乱蛋白（Dishevelled，Dsh或Dvl），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（T cell factor / lymphoid enhancer factor，TCF/LEF）相互作用，调节靶基因的表达，TCF/ LEF是一类具有双向调节功能的转录因子，它与Groucho结合抑制基因转录，而与结合β-catenin则促进基因转录。
Wnt还需要另外一个受体（co-receptor），即LRP5/6，属于低密度脂蛋白受体相关蛋白（LDL-receptor-related protein，LRP），但至今还不清楚它如何与Frz 一起活化Dsh。
Wnt信号途径可概括为（图8-34）：Wnt→Frz→Dsh→β-catenin的降解复合体解散→β-catenin积累，进入细胞核→TCF/LEF→基因转录（如c-myc、cyclinD1）。
β-catenin的降解复合体：主要由APC、Axin、GSK-3β、CK1等构成。
经典信号通路之Wnt信号通路
经典信号通路之Wnt信号通路1、Wnt信号通路简介Wnt信号通路是一个复杂的蛋白质作用网络，其功能最常见于胚胎发育和癌症，但也参与成年动物的正常生理过程.2、Wnt信号通路的发现Wnt得名于Wg (wingless) 与Int.wingless 基因最早在果蝇中被发现并作用于胚胎发育，以及成年动物的肢体形成INT 基因最早在脊椎动物中发现，位于小鼠乳腺肿瘤病毒(MMTV)整合位点附近。
Int-1 基因与wingless 基因具有同源性。
果蝇中wingless 基因突变可导致无翅畸形，而小鼠乳腺肿瘤中MMTV复制并整合入基因组可导致一种或几种Wnt基因合成增加。
3、Wnt信号通路的机制Wnt信号通路包括许多可调控Wnt信号分子合成的蛋白质，它们与靶细胞上的受体相互作用，而靶细胞的生理反应则来源与细胞和胞外Wnt配体的相互作用。
尽管发应的发生及强度因Wnt配体，细胞种类及机体自身而异，信号通路中某些成分，从线虫到人类都具有很高的同源性。
蛋白质的同源性提示多种各异的Wnt配体来源于各种生物的共同祖先。
经典Wnt通路描述当Wnt蛋白于细胞表面Frizzled受体家族结合后的一系列反应，包括Dishevelled受体家族蛋白质的激活及最终细胞核内β-catenin水平的变化。
Dishevelled (DSH) 是细胞膜相关Wnt受体复合物的关键成分，它与Wnt结合后被激活，并抑制下游蛋白质复合物，包括axin、GSK-3、与APC蛋白。
axin/GSK-3/APC 复合体可促进细胞内信号分子β-catenin的降解。
当“β-catenin 降解复合物”被抑制后，胞浆内的β-catenin得以稳定存在，部分β-catenin进入细胞核与TCF/LEF转录因子家族作用并促进特定基因的表达。
4、Wnt介导的细胞反应经典Wnt信号通路介导的重要细胞反应包括：癌症发生。
Wnts, APC, axin，与TCFs表达水平的变化均与癌症发生相关。
Wnt信号通路
wnt信号通路的生物学活性wnt信号通路（The Wnt signaling pathways）是复杂的生物信号转导结构网的一条。
其主要分为经典wnt信号途径和非经典wnt信号途径。
Wnt信号通路参与众多重要的生理病理过程，Wnt 通路调节造血干细胞及造血微环境，Wnt 通路参与控制神经前体细胞的增殖分化，在正常干/祖细胞池的保持方面有重要作用，且Wnt 信号通路与肿瘤的发生息息相关。
通过对wnt通路的研究，了解其对机体的影响，进一步针对其特征设计靶向药物是未来的研究重点。
关键词：wnt通路干细胞肿瘤生物活性WNT 名称来自于Wingless 和Int-1。
当缺失Wingless基因时，果蝇将无法长出翅膀，故命名为Wingless。
而Int-1 最早是作为老鼠乳腺癌的抑癌基因，当老鼠乳腺癌病毒占据Int-1 的结合位点时就会导致癌症的发生。
随着研究的不断深入，发现Wingless 和Int-1其实编码着同一种蛋白，故统一命名为WNT Wnt 信号途径是一类在生物体进化过程中高度保守的信号转导途径，调节控制着众多生命活动过程。
动物体早期发育中，Wnt 信号决定背腹轴的形成、胚层建立、体节分化、组织或器官形成等一系列重要事件；并直接控制着增殖、分化、极化、凋亡与抗凋亡等细胞的命运。
同时，Wnt 信号途径也与肿瘤发生密切相关。
在目前已知的癌症中，有十几种高发性癌变源于 Wnt 信号转导途径的失调。
根据 Wnt 蛋白转导信号的方式，人们又将 Wnt 信号转导途径分为经典 Wnt 信号途径（Canonical Wnt signal pathway）和非经典的 Wnt 信号途径（Noncanonical Wnt signal pathway）5-7。
2.1经典 Wnt 信号转导的分子机制经典 Wnt 信号途径也称为Wnt/β-catenin 信号途径。
在不同物种中 Wnt/β-catenin信号转导的分子机制具有极高的保守性。
细胞常见信号通路图片合集
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S6激酶调控蛋白质翻译(2004-7-17)•·eif2蛋白质翻译(2004-7-17)•·蛋白质翻译示意图(2004-7-17)•·线粒体凋亡通路(2004-7-17)•·死亡受体信号通路(2004-7-17)•·凋亡抑制通路(2004-7-17)•·细胞凋亡综合示意图(2004-7-17)•·Akt/Pkb信号通路(2004-7-17)•·MAPK/ERK信号通路(2004-7-17)•·哺乳动物MAPK信号通路(2004-7-17)•·Pitx2多步调节基因转录(2004-7-17)•·IGF-1R导致BAD磷酸化的多个凋亡路径(2004-7-17)•·多重耐药因子(2004-7-17)•·mTOR信号通路(2004-7-17)•·Msp/Ron受体信号通路(2004-7-17)•·单核细胞和其表面分子(2004-7-17)•·线粒体的肉毒碱转移酶（CPT）系统(2004-7-17)•·METS影响巨噬细胞的分化(2004-7-17)•·Anandamide，内源性大麻醇的代谢(2004-7-17)•·黑色素细胞（Melanocyte）发育和信号(2004-7-17)•·DNA甲基化导致转录抑制的机理图(2004-7-17)•·蛋白质的核输入信号图(2004-7-17)•·PPARa调节过氧化物酶体的增殖(2004-7-17)•·对乙氨基酚（Acetaminophen）的活性和毒性机(2004-7-17)•·mCalpain在细胞运动中的作用(2004-7-17)•·MAPK信号图(2004-7-17)•·MAPK抑制SMRT活化(2004-7-17)•·苹果酸和天门冬酸间的转化(2004-7-17)•·低密度脂蛋白（LDL）在动脉粥样硬化中的作用(2004-7-17)•·LIS1基因在神经细胞的发育和迁移中的作用图(2004-7-17)•·Pyk2与Mapk相连的信号通路(2004-7-17)•·galactose代谢通路(2004-7-17)•·Lectin诱导补体的通路(2004-7-17)•·Lck和Fyn在TCR活化中的作用(2004-7-17)•·乳酸合成图(2004-7-17)•·Keratinocyte分化图(2004-7-17)•·离子通道在心血管内皮细胞中的作用(2004-7-17)•·离子通道和佛波脂（Phorbal Esters）信号(2004-7-17)•·内源性Prothrombin激活通路(2004-7-17)•·Ribosome内化通路(2004-7-17)•·整合素（Integrin）信号通路(2004-7-17)•·胰岛素（Insulin）信号通路(2004-7-17)•·Matrix Metalloproteinases (2004-7-17)•·组氨酸去乙酰化抑制剂抑制Huntington病(2004-7-17)•·Gleevec诱导细胞增殖(2004-7-17)•·Ras和Rho在细胞周期的G1/S转换中的作用(2004-7-17)•·DR3，4，5受体诱导细胞凋亡(2004-7-17)•·AKT调控Gsk3图(2004-7-17)•·IL-7信号转导(2004-7-17)•·IL22可溶性受体信号转导图(2004-7-17)•·IL-2活化T细胞图(2004-7-17)•·IL12和Stat4依赖的TH1细胞发育信号通路(2004-7-17)•·IL-10信号通路(2004-7-17)•·IL 6信号通路(2004-7-17)•·IL 5信号通路(2004-7-17)•·IL 4信号通路(2004-7-17)•·IL 3信号通路(2004-7-17)•·IL 2 信号通路(2004-7-17)•·IL 18信号通路(2004-7-17)•·IL 17信号通路(2004-7-17)•·IGF-1信号通路(2004-7-17)•·IFN gamma信号通路(2004-7-17)•·INF信号通路(2004-7-17)•·低氧诱导因子（HIF）在心血管中的作用(2004-7-17)•·低氧和P53在心血管系统中的作用(2004-7-17)•·人类巨细胞病毒和MAP信号通路(2004-7-17)•·孕酮如何促进卵细胞成熟？(2004-7-17)•·How does salmonella hijack a cell (2004-7-17)•·Hop通路在心脏发育中的作用(2004-7-17)•·HIV-I Nef:负性调节fas和TNF (2004-7-17)•·HIV-1防止宿主细胞耐受的机理(2004-7-17)•·HIV诱导T细胞凋亡图(2004-7-17)•·血红素的伴侣分子(2004-7-17)•·g-Secretase介导ErbB4信号通路(2004-7-17)•·生物激素信号(2004-7-17)•·Granzyme A介导的凋亡信号通路(2004-7-17)•·G蛋白偶联信号需要Tubby支持(2004-7-17)•·糖酵解通路(2004-7-17)•·Ghrelin：食物吸收和能量平衡的调控者(2004-7-17)•·PS1能产生beta淀粉样蛋白导致老年性痴呆(2004-7-17)•·GATA3部分参与TH2细胞因子基因的表达(2004-7-17)•·GABA受体的代谢图(2004-7-17)•·FXR和LXR调节胆固醇代谢(2004-7-17)•·SLRP在骨骼中的作用(2004-7-17)•·自由基诱导细胞凋亡信号(2004-7-17)•·FOSB与药物成瘾(2004-7-17)•·fMLP诱导趋化因子基因表达(2004-7-17)•·Fibrinolysis通路(2004-7-17)•·糖酵解通路(2004-7-17)•·Fc Epsilon Receptor I信号(2004-7-17)•·FAS信号通路(2004-7-17)•·外源性Prothrombin激活通路(2004-7-17)•·真核细胞蛋白质翻译示意图(2004-7-17)•·雌激素反应蛋白EFP控制乳腺癌细胞的细胞周期(2004-7-17)•·EPO介导神经保护作用与NF-kB相关(2004-7-17)•·Erythrocyte分化通路(2004-7-17)•·Erk1/Erk2 Mapk 信号通路(2004-7-17)•·Erk和PI-3K在细胞外间质中的作用(2004-7-17)•·内质网相关的蛋白质降解通路示意图(2004-7-17)•·EPO售转导机制图(2004-7-17)•·血小板凝聚示意图(2004-7-17)•·NDK动力学(2004-7-17)•·线粒体的电子传递链示意图(2004-7-17)•·Eicosanoid代谢(2004-7-17)•·EGF信号通路(2004-7-17)•·calcineurin对Keratinocyte分化的影响(2004-7-17)•·E2F1信号通路(2004-7-17)•·MTA-3在雌激素不敏感性乳腺癌中下调(2004-7-17)•·双链RNA诱导基因表达示意图(2004-7-17)•·Dicer信号通路（RNAi机理）(2004-7-17)•·CDK5在老年性痴呆中的调节作用(2004-7-17)•·树突状细胞调节TH1和TH2发育示意图(2004-7-17)•·RAR和RXR被蛋白酶体降解通路(2004-7-17)•·D4-GDI信号通路示意图(2004-7-17)•·细胞因子和炎症反应示意图(2004-7-9)•·细胞因子网络调控图(2004-7-9)•·CFTR和beta 2肾上腺素受体通路(2004-7-9)•·Cyclin和细胞周期调控图(2004-7-9)•·Ran核质循环转运图(2004-7-9)•·Cyclin E降解通路图(2004-7-9)•·CXCR4信号通路图(2004-7-9)•·CTL介导的免疫反应图(2004-7-9)•·CTCF：第一个多价核因子(2004-7-9)•·皮质激素和心脏保护(2004-7-9)•·骨骼肌的成肌信号图(2004-7-9)•·VitD调控基因表达信号图(2004-7-9)•·补体信号通路(2004-7-9)•·线粒体和过氧化物酶体中β氧化的比较图(2004-7-9)•·经典的补体信号通路图(2004-7-9)•·心律失常的分子机制图(2004-7-9)•·hSWI/SNF ATP依赖的染色体重塑(2004-7-9)•·碳水化合物和cAMP调节ChREBP图(2004-7-9)•·分子伴侣调节干扰素信号图(2004-7-9)•·Ceramide信号图(2004-7-9)•·局部急性感染的细胞与分子信号(2004-7-9)•·细胞与细胞粘附信号(2004-7-9)•·细胞周期G2/M调控点信号调节(2004-7-9)•·细胞周期 G1/S调控点信号图(2004-7-9)•·CDK调节DNA复制(2004-7-9)•·cdc25和chk1在DNA破坏中的作用图(2004-7-9)•·CD40L信号通路图(2004-7-9)•·CCR3信号图(2004-7-9)•·CBL下调EGF受体的信号转导图(2004-7-9)•·一些氨基酸的代谢通路图 3 (2004-7-9)•·一些氨基酸的代谢通路图 2 (2004-7-9)•·一些氨基酸的代谢通路图(2004-7-9)•·Catabolic pathway for asparagine and asp (2004-7-9)•·Caspase 信号级联通路在细胞凋亡中的作用(2004-7-9)•·CARM1和雌激素的信号转导调控(2004-7-9)•·抗氧自由基的心脏保护作用信号转导图(2004-7-9)•·乙肝病毒中的钙信号调控(2004-7-9)•·镉诱导巨噬细胞的DNA合成和增殖(2004-7-9)•·Ca2+/CaM依赖的激活(2004-7-9)•·B细胞活化机理图(2004-6-9)•·BTG家族蛋白和细胞周期的调节(2004-6-9)•·BRCA1作用机理(2004-6-9)•·骨重塑示意图(2004-6-9)•·Botulinum Toxin阻断神经递质释放示意图(2004-6-9)•·缬氨酸的生物合成图(2004-6-9)•·Tryptophan在植物和细菌内的生物合成(2004-6-9)•·苏氨酸和蛋氨酸的体内合成示意图(2004-6-9)•·sphingolipids生物合成(2004-6-9)•·spermidine和spermine生物合成(2004-6-9)•·细菌体内合成脯氨酸的示意图(2004-6-9)•·苯丙氨酸和酪氨酸的生物合成(2004-6-9)•·神经递质的合成示意图(2004-6-9)•·赖氨酸生物合成图(2004-6-9)•·亮氨酸的体内生物合成图(2004-6-9)•·异亮氨酸的生物合成图(2004-6-9)•·甘氨酸和色氨酸的生物合成(2004-6-9)•·Cysteine在哺乳动物中的合成图(2004-6-9)•·Cysteine在细菌和植物内生物合成图(2004-6-9)•·Chorismate在细菌和植物内的生物合成(2004-6-9)•·Arginine在细菌内的生物合成(2004-6-9)•·生物活性肽诱导的通路(2004-6-9)•·脂肪酸的β氧化通路(2004-6-9)•·BCR信号通路示意图(2004-6-9)•·SUMOylation基本机理(2004-6-9)•·PPAR影响基因表达的基本信号机制图(2004-6-9)•·B淋巴细胞表面分子示意图(2004-6-9)•·B细胞生存信号通路(2004-6-5)•·B细胞信号通路的复杂性(2004-6-5)•·GPCR信号的衰减的机理(2004-6-4)•·ATM信号通路(2004-6-4)•·阿斯匹林的抗凝机理(2004-6-4)•·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(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蛋白耦联受体的关系(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(2004-6-4)•·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, theWiskott-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), 790-3Falet 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 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 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 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)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 thatpost-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 veryactive 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.视觉信号转导信息来源：本站原创生物谷网站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. Rhodopsinin 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，低氧信息来源：本站原创生物谷网站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 tubularsystem 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诱导细胞凋亡信息来源：本站原创生物谷网站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信号转导信息来源：本站原创生物谷网站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 TrkAthrough 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信息来源：本站原创生物谷网站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.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甲基化信息来源：本站原创生物谷网站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。
wnt信号通路
Wnt信号通路是广泛存在于多细胞真核生物中的一条高度保守的信号通路，在胚胎发育过程中起到重要作用，例如促进神经祖细胞的增殖，抑制其分化。
在对Wnt信号通路的研究中，其他信号通路与Wnt信号通路之间的相互作用也成为近年来研究的热点。
中科院上海生命科学研究院生化与细胞所李林研究组最新研究揭示了NFAT蛋白调控经典Wnt信号通路的分子机制，及其在神经祖细胞增殖和分化过程中的功能。
博士研究生黄涛等人发现，NFAT这一钙信号的重要下游分子在钙信号的调节下，与Dvl这一经典Wnt信号通路的重要分子存在相互作用。
在细胞核内，NFAT通过与Dvl的相互作用，抑制Dvl与β-catenin的相互作用，从而影响转录复合物(Dvl-β-catenin-TCF-c-Jun)的形成，进而起到抑制经典Wnt信号通路的作用。
进一步的工作还发现，在鸡胚神经管发育的过程中，NFAT通过对经典Wnt 信号的抑制，从而抑制神经祖细胞的增殖，促进神经细胞的分化。
该研究首次详细阐明了NFAT对经典Wnt信号产生抑制的分子机制，并揭示了NFAT在神经祖细胞分化过程中的重要作用。
该项工作与景乃禾研究组合作完成，并得到了科技部、国家自然科学基金委、中国科学院以及上海市科委的经费支持。
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KEGG上的信号通路图怎么看
KEGG上的信号通路图怎么看？提示：请点击标题下方蓝色“实验万事屋”，添加关注后，发“嗯”可以查看我们之前的文章。
未经允许，其他公众号不得转载哦！想要把自己研究的分子扯上明星分子或者明星通路？那是不难，难的是具体到底要怎么去扯，芯片结果啊，生信结果啊，都会给你提示，但真的要具体扯上去，还得看懂那些七七八八的信号通路图。
KEGG Pathway上有着大量的信号通路图，画得一个复杂啊！巨坑爹有没有？曾经有师弟说我之前曾经把Wnt通路描述错了，他师兄告诉他，应该是GSK-3β磷酸化抑制β-Catenin降解，并促进它入核的。
在这里，我们只能默默地祝福这位师兄了……那我们就用Wnt通路来做例子吧。
先上KEGG下载一个Wnt的信号通路图，如下：绝壁是很高大上的不是么？这要咋看呢？其实这张图上把三个Wnt通路都画上去了，也就是Wnt/β-Catenin（经典Wnt通路），Wnt/PCP（平面的细胞极性途径）和Wnt/Ca2+（Wnt/钙离子）三条信号通路组成，我们就删减一下，就光看经典的Wnt通路，就变成了下面这个模样：感觉还是很高大上有木有？那就再删减一下，把它变成经典Wnt信号通路的骨架会是什么样呢？就是这样：简洁明快了吧，但要怎么来看懂这样的图呢？我们来看一下KEGG Pathway的具体图例：把这些图例用来解释经典Wnt信号通路骨架图，就变成了：看懂了么？那给你从左到右解释一下：1）Wnt激活膜上受体，将信号传递到第二信使Dvl，活化的Dvl抑制由Axin、APC 和GSK-3β组成的复合物的活性,使β-catenin不能被GSK-3β磷酸化。
2）磷酸化的β-catenin才可通过泛素化(ubiquitination)而被胞浆内的蛋白酶体所降解，由于非磷酸化的β-catenin不能被蛋白酶体降解，从而导致β-catenin在胞浆内积聚，并移向核内。
3）当游离的β-catenin进入细胞核内，即可与转录因子TCF/LEF结合，激活TCF 转录活性，调节靶基因的表达。