Axin在Wnt信号转导途径中的作用

ＩｓｓＮ１００７．７６２６中国生物化学与分子生物学报堡堡望竺堕！殳坚婆壁堂堡螋逸堡壁翌垒趟熬尘塑望！望曼ｉ然！錾逻２００６年４月！登！！：！！：！！里兰二望！·综述·Ａｘｉａ在Ｗ哦信号转导途径中的作用金利华¨，李勤喜，叶志云”３６ｌ∞５）（覆门大学生令秘学学篦，麓门摘要Ｗｎｔ信号转导途径是细胞形状、运动、黏附、增殖、分化、癌变及机体发育等过程的主要途径之一。血遍（轴萤由）是一个体轴发育抑制域子，作为稳架蛋白在Ｗｎ￡信号转导途径申起蓦荧键的作瘸．Ａｘｉｎ通过不同的祝裁调节￥连环蛋白的磷酸化和稳定性．它通过与Ａ茂、ＧＳＫ．３８、￥逢环蛋白和ｃＫＩａ结合形成复合体促进口连环蛋白的降解，还通过同源二聚化、核质穿梭、自身磷酸化和稳定性的来调节８连环蛋白的稳定性．Ａｘｉｎ通过ｗｎｔ信号转导途径参与了一系列生物学效应的诵控，如体骚发畜、缎脆死亡、神经元秘分纯等．作势一个馥发现戆牌瘸抑期嚣子，瘫珏将为癌症的诊断和治疗提供新的有效的手段．关键词ａｘｉｎ；Ｗｎｔ；信号转导中图分类号０７８ＲｏｌｅｓｏｆＡｘｉｎｉｎｔｈｅＷｎｔＳｉｇｎａｌｉｎｇｐａｔｈｗａｙＪＩＮ【ｊ—Ｈｕａ”，ＭＱｉｎ—ｘｉ，ＹＥＺｈｉ．Ｙｕｎ”（＆矗巅移删爸＆谗嬲，殿８懈碍渤妇嚣毋，簌＃粼ｎ３６ｌ００５，蕊溉）ＡｂｓｔｒａｃｔＴｈｅＷｎｔｓｊｇｎａｌｉｎｇｐａｔｈｗａｙｐｌａｙｓｉ珈ｐｏｒｔａｎｔＩ试ｅｓｉｎｃｅｌｌｓｈａｐｅ，ｃｅｌｌｍｏｖｅｍｅｎｔ，ｃｅｌｌａｄｈｅｓｉｏｎ，ｃｅｌｌｄｉｆｆ色ｌ群ｎｔｉａｔｉｏｎ，ｐｒ０１ｉｆｅｒａｔｉｏｎａｎｄｐｒｏｔｅｉｎ，ｉｔｐｌａｙｓｏｎｃｏｇｅｎｅｓｉｓａｎｄｄｅｖｅｌｏｐｍｅｎｔ．Ａｘｉｎｉｓａｘｉｓｉｎｈｉｂｉｔｏｒ．Ａｓｓｃａｆｂｌｄｃｒｉｔｉｃａｌ１．ｏｌｅｉｎｔｈｅＷｎｔｓｉｇｎａｌｉｎｇｐａｔｈｗａｙ．Ａｘｉｎｒｅｇｕｌａｔｅｓｔｈｅｐｈｏｓｐｈｏｒｙｌａｔｉｏｎａｎｄｓｔａｂｉｌｉｔｙｏｆ瑟－ｃ戳ｅ瓣ｊ秘ｖ遮ｄｉ董强孢ｎ｜ｍｅｃｈａ珏ｉｓ掇ｓ．魏蠡ｅｉｌｉ｜ａ￡ｅｓ零一ｅ８圭ｅ珏ｉ珏丧；ｇ糯蘸ａｔｉｏ珏酚ａｓｓｅｍｂｌｉ珏ｇａ茹一ｅａｌｅ珏主珏ｄｅｓｔ粼ｅｌｉｏｎｃｏｍｐｌｅｘｉｎｃｌｕｄｉｎｇＡＰＣ，ＧｓＫ一３８，８一ｅａｔｅｎｉｎ，ｃＫＩａａｎｄａ）【ｉｎｉｔｓｅｌｆ，弧ｅｈｏｍｏ（重ｉ瑚ｌｅＩｉｚａｔｉｏｎ，ｎｕｃｌｅａｒ—ｃｙｔ叩ｌａｓｍｉｃｓｈｕｔｔｌｉｎｇ，ｐｈｏｓｐｈｏｒｙｌａｔｉｏｎａｎｄｓｔａｂｉｌｉｔｙｏｆａｘｉｎｉｔｓｅｌｆａＩｓｏｐｌａｙｉ“ｌｐｏｒｔａｎｔｒ０１ｅｓｉｎｐ—ｃａｔｅｎｉｎｒｅｇｕｌａｔｉｏｎ．１ｎｔｈｅＷｎｔｓｉ｛弘ａｌｉｎｇｐｆｏＶｉｄｅｐａｔｈｗａｙ，ａｘｉｎｐａＩｔｉｃｉｐａｔｅｓｉｎｔｈｅｒｅｇｕｌａｔｉｏｎｓｏ珏。Ａｓｏｆｓｅｒｉｅｓｏｆｂｉｏｌｏｇｉｅａｌｅｆ孙ｃｔｓｔｌ王壬珏ｏｒｓｕｃｈａｓａｘｉｓｄｅ￥ｅｌｏｐｍｅｎ￡，￡ｅｌｌａｄｅａ氇，ｎｅｌｌ∞ｎ奎ｄｉ垂孙ｒｅ嫩ｉ戤ｉｏｎ黼纛ｓｏｍｅａｎｓａ珏ｅ旗ｙｒｅｅｏ辨ｉｚｅｄｓ娃ｐｐ弛ｓｓｏｒ，ａｘｉ秘ｗｉｌｌｎｅｗｌｙｉｍｐａｅｔｆｕｌｆｏｒｄｉａｇｎｏｓｉｓａｎｄｔｈｅｒａｐｙｏｆＫｅｙ、】．咐ｒｄｓａｘｉｎ；Ｗｎｔ；ｓｉｇｎａｌｉｎｇｔｒａｎｓｄｕｃｔｉｏｎ缨照信号转导是当今生兹医学研究领域最前沿、最活跃的主题之一。ｗｎｔ信号转导途径由一系列癌基因和抑癌基因编码的蹑白质组成，各种蛋白质之间彼此联系、棱互制约，在细胞增殖、分化、运动、黏附及视俸发育等过程中起着重要调节作用Ⅲ．Ａｘｉｎ（轴蛋白）是一个体轴发育抑制因子（ａｘｉ８ｉｎｈｉｂｉｔｏｒ），也是一个肿瘤抑制因子，它谢一系列结合位点，作为檎架蛋自，麓与ｗｎｔ信号转导途径熬许多重要成员相互结合，在个体发育、细胞增殖及癌变等过程中起着关键作用㈦ｏ．目前，有关ａ）【ｉｎ在ｗｎｔ信号途径中的调节功能及其貔理研究是肿瘤信号转导领域的焦点之一。收稿日期：２００５—０９一１９．接受日期：２００５．１２。２ｌ福建省擞大科技项目（Ｎｏ．２００２瑚２）资助”联系人强ｌ＆ｆ奴：８６，５９２—２１８４６８７；¨褒在魏蟪：厦门大学生物医学工程瓣究中心，覆门３６ｌ∞５Ｅ—ｍａｉｌ：ｙｚｙｌ８９３＠ｘｍｕ．ｅｄｕ．ｃｎＲｅｃｅｉｖｅｄ：Ｓｅｐｔｅｒｎｂｅｒｓｕｐｐｏｒ№ｄ１９，２００５；Ａｃｃｅｐｔｅｄ：ＤｅｃｅｍｂｅｒＫｅｙＲｅｓｅａｒｃｈＰｒｏＦａｍ８２ｌ，２００５Ｐｒｏｖｉｎｃｅｂｙｔｈｅ《ｆ两ｉａｎ（Ｎｏ．２∞２ｆ静０２）．＋Ｃｏｒｒｅ８ｐｏｎｄｉｎｇａｕｔｈｏｒ１斟＆Ｆ瓤：８６—５９２“２１８４６８７；Ｅ－ｍａｉｌ：ｙｚｙｌ８９３＠ｘｍｕ．ｅｄｕ．ｃｎ１’胁ｓｅｍａｄｄｒｅｓｓ：Ｒｅ∞ａｆｅｂＣｅｎｔｅｒ《Ｂｉｏｍｅｄｉｅ建Ｅｎｇｉｎｅｅ蛀醒，ＸｉａｍｅｎＵｎｉｖｅｆｓｉ￡ｖ，Ｘｉｍｅｎ３６１１００５，ｅｈｉｎａ万方数据　２９０中国生物化学与分子生物学报２２卷１Ａ嫡ｎ的发现似汛是１９９７年从一种称为Ｆｕｓｅｄ的小鼠突变结合区域（ａａ３５３～４３７）凹Ｊ、Ｄｉｖｅｒｓｉｎ结合区域（ａａ。４３７）㈨、ＬＲＰ结合区域（ａａ３５３３５３～４３７）…’１２］、Ｉ一曲结合区域（ａａ３８５～４６８）ｎ３Ｉ、ｐ连环蛋白（ｐ—ｃａｔｅｎｉｎ）结合区域（ａａ４３７—５０６）旧１、ａｘｉｎ结合分子ａ】【ａｍ（ａ】【ｉｎ株中克隆到的基因ｂｊ．嬲沉突变的纯合子胚胎会产生双向体轴ｎ］，说明ａ）（ｉｎ在体轴形成过程中起着负调节的作用．事实上，把ａｘｉｎ注入非洲爪蟾胚胎中，大部分胚胎表现出很强的体轴缺陷表型ｂｏ．不同的生物化学方法都证实了ａ】【ｉｎ在不同物种中的存在ｕ’４０．从果蝇、爪蟾、鸡、小鼠到人类，ａｘｉｎ都是十分保守的．ａｘｉｎ普遍表达于不同的组织，包括脑、胸腺、心脏、肺、肝、脾和肾等．人类染色体中表达ａｘｉｎ的似讥１基因定位于第１６条染色体的长臂上（１６口１３．３），其编码区由１０个外显子组成，编码含８６２个氨基酸残基的ａｘｉｎ蛋白¨’４０．鼠ａ】【ｉｎ蛋白（ｒ．ａ）【ｉｎ）由８３２个氨基酸残基组成．ａｓｓｏｃｉａｔｉｎｇ啪ｌｅｃｕｌｅ）结合区域（强５０７～７１２）¨４“６Ｉ、Ｄｉｓｈｅｖｅｌｌｅｄ（简称Ｄｖｌ或Ｄｓｈ）结合区域（ａａ８２０，即ＤⅨ结构域（Ｄｉｓｈｅｖｅｌｌｅｄ／ａ）（ｉｎ５３０～７１２，７５７～７５７～８２０）口７’１８］、ａ】【ｉｎ形成寡聚体的区域（ａａｈｏｍ０１０９０ｕｓｄｏｍａｉｎ））№１．其中Ｎ末端ＡＰｃ结合区域的氨基酸序列与Ｇ蛋白信号调节因子ＲＧｓ４（ｒｅｇｕｌａｔｏｒｐｍｔｅｉｎｏｆＧ—ｓｉｇＩｌａｌｉｎｇ）的５８～１７８位氨基酸残基有３１％的相同性，这一结构域在Ｇ蛋白信号因子家族中高度保守，所以称为ＲＧｓ结构域Ｈ１．ａＸｉｎ形成寡聚体的ｃ末端７５７～８２０位氨基酸残基与鼠Ｄｖｌ同源物Ｄｖｌ．１的第８～７３个氨基酸残基有３７％的相同性，称为ＤⅨ结构域Ｈ１．最近又有新发现突触构架分子ｓ．ｓｃＡＭ（ｓｙｎ印ｔｉｃｓｃａｆｆｏｌｄｉｎｇｍｏｌｅｃｕｌｅ）能与ａ）【ｉｎ的ＧｓＫ．触ｉｎ含有与ｗｎｔ信号途径中许多成员相互结合的功能区域∽１，如：肿瘤抑制因子肠腺息肉瘤蛋白ＡＰＣ（ａｄｅｎｏｍａｔｏｕｓｐｏｌｙｐｏｓｉｓｃｏｌｉ）的结合区域（氨基酸残基３ｊ３结合区域直接结合¨９｜；周期蛋白依赖的蛋白激酶ｃＤＫ２（ｃｙｃｌｉｎ．ｄｅｐｅｎｄｅｎｔｋｉｎａｓｅ８９～２１６，即ＲＧＳ结构域）ｂｏ、蛋白磷酸酶ＰＰ２ＡＩ）结合区域２）能通过ａ）【ｉｎ的Ａｒｇ．（ｐｒｏｔｅｉｎｐｈｏｓｐｈａｔａｓｅ２Ａ）结合区域（ａａ２９８～５０６／５０８～ｘ．Ｌｅｕ（ＲｘＬ）位点与ａ）【ｉｎ结合㈣１．舨ｉｎ与这些蛋白的接合模式如Ｆ阮１怛ｏ．７１２）拍ｏ、酪蛋白激酶ｃＫＩ（ｃａｓｅｉｎｋｉｎａｓｅ（ａａ２１７—３５２／５０８—７１２）ｏＬ…、糖原合成激酶ＧｓＫ．３１３Ｆｉｇ．１ＩＩｌｔｅｒ觚ｔｉｎｇｍｏｄｅｌｏｆａｘｉＩｌｗｉｔｌｌｃ哪ｐｏｎｅｎｔｓｏｆｔＩ地ｗｎｔｓｉ印ａｌｉｌＩｇｐａｔｌｌｗａｙ（Ｒｅｆｅｒｅｎｃｅ［２］）２Ｗｎｔ信号转导途径ｗｎｔ是一个富含半胱氨酸的分泌型配体家族，解，因此细胞内的Ｂ连环蛋白总保持较低的水平心１’２２｜．当ｗｎｔ配体与其细胞表面受体蹦ｚｚｌｅｄ结合，ｗｎｔ信号途径被激活时，晒ｚｚｌｅｄ激活Ｄｖｌ，Ｄｖｌ再激活下游因子ＧｓＫ一３ｐ结合蛋白ＧＢＰ（ＧｓＫ一３Ｂｂｉｎｄｉｎｇ在果蝇里称为俩ｎ９１ｅｓｓ．ｗｎｔ信号转导途径是在对果蝇极性发育的遗传分析和爪蟾的胚胎体轴形成研究中发现的．这一信号途径从果蝇、爪蟾到哺乳动物等不同物种中都非常保守．ｗｎｔ在细胞增殖、细胞形态、细胞黏附、细胞运动、机体发育、分化等过程中起着重要调节作用¨’４Ｊ．正常情况下，细胞质内ｃＫＩａ和ＧｓＫ一３Ｂ依次将Ｊ３连环蛋白磷酸化，磷酸化的Ｂ连环蛋白能被泛素（ｕｂｉｑｕｉｔｉｎ）识别并泛素化，然后被蛋白酶复合体水ｐｍｔｅｉｎ），激活的ＧＢＰ能识别并抑制ＧｓＫ一３ｐ的磷酸化活性，使ＧｓＫ一３口不能磷酸化ｐ连环蛋白，导致ｊ３连环蛋白不能被泛素识别，从而不能被蛋白酶复合体降解汜２｜．在细胞质中没有被降解而过量积累的Ｂ连环蛋白会转移到细胞核内，与核内转录因子ＬＥＦ／ＴｃＦ家族成员结合，刺激ｃ－ｍｗ、吖ｃ砌Ｄｌ、．胁ｌ、ｃ－皿ｎ等一系列癌基因的表达，引起细胞异常增殖，最终致使细胞发生癌变心引．万方数据　第４期金利华：Ａｘｉｎ在ｗｎｔ信号转导途径中的作用２９１３Ａｘｉｎ在Ｗｎｔ信号转导途径中的作用Ａｘｉｎ以构架蛋白的形式在ｗｎｔ信号转导途经中起负调节作用‘１Ｉ，如Ｆｉｇ．２．ｗｎｔ信号途径中，ａ】【ｉｎ的ＲＧｓ结构域㈨、ｐ连环蛋白结合区域和ＧｓＫ．３Ｂ结合区域‘２５１以及ｃ末端ＤＩｘ结构域‰１对调节Ｂ连环蛋白水平是至关重要的．Ｆｉｇ．２Ｒｏｋｓｏｆａ菇ｎｉｎⅡ塘Ｗｎｔｓｉｇ衄Ｕｎｇｐａｔｈｗａｙ３．１ｐ连环蛋白降解复合体有２个主要因素影响８连环蛋白的磷酸化：其一，依靠ａｘｉｎ的构架作用将ｃＫＩ、ＧｓＫ一３Ｂ和ｐ连环蛋白装配在一起；其二，ｃＫＩ对｜３连环蛋白Ｓｅ∥的起始磷酸化作用．Ａｘｉｎ作为构架蛋白，将ＡＰｃ、ＧＳＫ．３ｐ、８连环蛋白、ｃＫＩａ组合起来形成』３连环蛋白降解复合体，促进｜３连环蛋白的磷酸化及降解旧ｑ…．ＡＰｃ是在家族性大肠息肉腺瘤的研究中发现的，在ｗｎｔ／０连环蛋白信号途径中起负作用，它在胞质中与Ｄ连环蛋白结合，促进ｐ连环蛋白降解．还能通过自身的核质穿梭，调节｜３连环蛋白的定位和降解‘３０’”Ｊ．实验表明，结肠癌细胞中过量表达ａｘｉｎ会明显促进Ｇ连环蛋白的降解；相比之下，缺失ＡＰｃ结合区域的ａｘｉｎ突变体就失去了这一功能，说明ａｘｉｎ的ＡＰｃ结合区域，即ＲＧｓ结构域对其下调１３连环蛋白是必需的∽４Ｉ．而且，与ＡＰｃ结合的ａ】【ｉｎ比ａ］（ｉｎ自身能更有效地诱导｜３连环蛋白的降解怛３Ｉ，说明ＡＰｃ对ａｘｉｎ下调Ｊ３连环蛋白水平同样起着关键的作用．同样，ＡＰＣ也需要与ａｘｉｎ结合才能负Ｊ３连环蛋白．ＡＰｃ与ａｘｉｎ形成复合体能促进ＧｓＫ．３Ｂ对８连环蛋白的磷酸化ｂ２Ｉ．一旦ＡＰＣ上与ａｘｉｎ结合的区域被破坏，ＡＰｃ就失去了促进Ｊ３连环蛋白降解的能万　方数据力阳３Ｉ．ａ】【ｉｎ还能通过与之结合的ｃＫＩ￡促进ＡＰｃ的磷酸化．ＡＰｃ上Ｂ连环蛋白调节位点发生突变会影响ＡＰｃ依赖ａｘｉｎ的ｃＫＩ￡磷酸化作用，使ＡＰｃ对８连环蛋白的调节能力降低Ⅲ１．如果只对ＡＰＣ的Ｇ连环蛋白结合区域进行突变，而其ａｘｉｎ结合区域还保持完好，同样会使ＡＰｃ失去促进｜３连环蛋白降解的能力．所以ＡＰｃ必须与ａＸｉｎ和Ｂ连环蛋白同时结合才能有效地促使｜３连环蛋白降解．ＣＫＩ和ＧＳＫ一３Ｂ对ＡＰＣ的磷酸化提高了ＡＰｃ与ｐ连环蛋白的亲合性．对ＡＰｃ与ｐ连环蛋白结合体的晶体结构分析表明，ＡＰｃ上Ｂ连环蛋白结合位点的磷酸化是由ｃＫＩ和ＧｓＫ一３ｊ３互相合作引导进行的，ａｘｉｎ在该磷酸化中起构架蛋白作用．Ａｘｉｎ与磷酸化的ＡＰｃ竞争地结合在８连环蛋白的同一面ｂ５＿７Ｉ．ｘｉｎｇ等人对ｐ连环蛋白与ａ】（ｉｎ．ｃＢＤ（ｐ．ｃａｔｅｎｉｎｂｉｎｄｉｎｇｄｏ啪ｉｎ，矧ｎ的ｐ连环蛋白结合区域）结合体的晶体结构分析发现，ａＸｉｎ—ｃＢＤ形成一个ａ螺旋，占据了Ｂ连环蛋白的第３、４个ａｍａｄｉｌｌｏ重复序列形成的沟槽，阻止了Ｂ连环蛋白的其它结合蛋白在这里的结合．当ＡＰｃ被磷酸化后，就会与ａｘｉｎ竞争性地结合在ｐ连环蛋白上．推测ＡＰｃ在调节口连环蛋白过程中的另一关键作用就是将磷酸化的｜３连环蛋白从ａｘｉｎ／ＡＰｃ／ＧｓＫ．３ｐ复合体中转移出去，使ｐ连环蛋白被泛素化从而降解旧８｜．ｃｈｏｉ等人发现，ＡＰｃ自身水平也能通过泛素一蛋白酶复合体下调．在ＡＰｃ的泛素化及降解过程中，商ｎ通过ＤＩｘ区域形成自身寡聚体促进这一泛素化降解作用旧…．在Ｓｗ４８０细胞中缺失Ｂ连环蛋白结合区域的ａ）【ｉｎ突变体不能下调ｐ连环蛋白．同样，缺失ＧｓＫ一３ｐ结合区域的ａｘｉｎ突变体也丧失下调Ｊ３连环蛋白的功能㈨ｏ．说明ａｘｉｎ必须同时与１８连环蛋白和ＧＳＫ．３１３结合才能下调１３连环蛋白水平．这些都说明了通过ａｘｉｎ形成ａＸｉｎ／ＡＰｃ／ＧｓＫ一３Ｂ／Ｂ—ｃａｔｅｎｉｎ／ｃＫＩａ降解复合体的重要性．Ａｘｉｎ的ＤＩＸ结构域Ａｘｉｎ通过其ｃ末端形成同源寡聚体．Ａｘｉｎ如果缺失了ｃ末端，即使它能结合ＧｓＫ一３１３和ｐ连环蛋白，也不能下调胞内』３连环蛋白水平．用不相关的二聚分子类维生素Ａｘ受体ＲｘＲ（ｒｅｔｉｎｏｉｄｘｒｅｃｅｐｔｏｒ）最近，在斑马鱼中又发现一种新的含有ＤＩｘ结３．２代替ｃ末端使ａＸｉｎ重新二聚化之后，就能恢复其负的功能怛５。．故通过ｃ末端形成寡聚体是ａｘｉｎ调节ｊ３连环蛋白所必需的．２９２中国生物化学与分子生物学报２２卷构域的蛋白ｃｃｄｌ．它能通过ＤⅨ结构域与Ｄｖｌ和ａｘｉｎ形成同源和异源寡聚体，激活依赖ＴｃＦ转录因子的转录Ｈ１Ｉ．斑马鱼胚胎中过量表达ｃｃｄｌ会导致前脑和眼睛变小．这与ｗｎｔ８基因的过量表达产生的效果一致．但是显性负作用的ｃｃｄｌ（ＤＮ．Ｃｃｄｌ）却会导致相反的效果．而且ｃｃｄｌ诱导的ｗｎｔ活性表型能够被ａｘｉｎ或ＤＮ．ｃｃｄｌ的表达抑制，说明ｃｃｄｌ是在ｗｎｔ受体下游和ａＸｉｎ的上游发挥作用的ｍ’４３］．但是ａｘｉｎ在ｗｎｔ信号途经中的作用是否要受ｃｃｄｌ的还不清楚．３．３心ｎ的核质穿梭对ｐ连环蛋白的影响对果蝇的遗传学研究表明，ａＤｃｉｎ除了在细胞质中作为构架蛋白形成复合体增强Ｂ连环蛋白的降解以外，还存在另外一个与此的机制下调Ｂ连环蛋白水平：它能通过核质穿梭，促进８连环蛋白定位于细胞质㈨椰ｏ．Ａｘｉｎ具有核输出信号序列ＮＥｓ（ｎｕｃｌｅａｒｅｘｐｏｒｔｓｅｑｕｅｎｃｅ）（ａａ５３８～５４７）和ｃ末端双向的核定位序列ＮＬＳ（ｎｕｃｌｅａｒｌｏｃａＨｓａｔｉｏｎｓｉｇｎａｌｓｅｑｕｅｎｃｅ）（ａａ８４９—８６５）．核质穿梭的ａ）【ｉｎ作为一种分子伴侣，协同Ｇ连环蛋白在细胞核或者细胞质中的分布．当用出核通路特异抑制剂ｌｅｐｔｏｍｙｃｉｎＢ处理细胞时，ａｘｉｎ便不能自由进行核质转移，积累于细胞核内‘４３．４不同的ｗｎｔ受体对ｐ连环蛋白的调节ｗｎｔ能通过Ｄｖｌ来抑制ａＤｃｉｎ多蛋白复合体的活动．ｃｌｉｆｆｅ等人研究表明，ｗｉｎ９１ｅｓｓ信号能使果蝇中ａＸｉｎ从细胞质转移到细胞膜，这一转移过程依赖于细胞质中的ＤｖｌＨ“．Ｄｖｌ使ａｘｉｎ重新分布是ｗｎｔ信号通过ａｘｉｎ调节Ｊ３连环蛋白的机理之一．除了七重跨膜受体蛋白Ｆｒｉｚｚｌｅｄ家族能接受ｗｎｔ信号，单重跨膜蛋白ＬＲＰ家族（ＬＤＬ—ｒｅｃｅＤｔｏｒ－ｒｅｌａｔｅｄｐｒｏｔｅｉｎ５，６／Ａｒｒｏｗ）也能接受并转导ｗｎｔ信号。４…．Ｍａｏ等人发现ａｘｉｎ与ＬＲＰ５的胞内部分结合，该结合将ａｘｉｎ拉到细胞膜处‘１２Ｉ．Ｔｏｌ衍ｎｓｋｉ等人又发现Ａ盯ｏｗ能将ａｘｉｎ拉到细胞膜处，导致ａｘｉｎ的降解，使胞内没有足够的ａｘｉｎ参与Ｂ连环蛋白的降解作用，从而加强了胞内｜３连环蛋白的积累Ｈ８Ｉ．ＬＲＰ５，６／Ａ啪ｗ与Ｆｒｉｚｚｌｅｄ在功能上是合作受体的关系∽’５共同调节ａｘｉｎ的降解．所以ａＤｃｉｎ蛋白的稳定性也是它在ｗｎｔ信号转导途径中的调节机制之一．３．５ＧＳＫ．３ｐ和ＣＤＫ２对ａｘｉｎ的磷酸化作用Ａｘｉｎ在ｗｎｔ信号途径中作为构架蛋白，促进ＧｓＫ一３Ｂ对Ｂ连环蛋白的磷酸化作用．在这个过程中，ＧｓＫ一３｜３同样使ａｘｉｎ自身发生磷酸化．磷酸化的万　方数据ａｘｉｎ增加了它与｜３连环蛋白的亲合性ｂｈ５２｜．ｒ－ａｘｉｎ的ＳＡＮＤＳＥＱＱＳ３３０、ＳＤＡＤＴＬｓＬｒＩｄ４１和ＳＬＴＤＳ３４３可能就是ＧＳＫ．３１３对ａ）【ｉｎ的磷酸化位点心３’．Ａｘｉｎ被磷酸化后稳定性增强．因此ＧＳＫ．３８对ａｘｉｎ和ｐ连环蛋白的磷酸化作用导致两个相反的结果：对ａｘｉｎ的磷酸化使其稳定，而对１３连环蛋白的磷酸化使其降解．ａＸｉｎ作为构架蛋白，其稳定性增强也更加有利于它促进Ｂ连环蛋白的降解”３｜．Ｋｉｍ等人研究表明，ｃＤＫ２能通过ａｘｉｎ的Ａｒｇ．ｘ．Ｌｅｕ位点与ａｘｉｎ结合，并且ｃｙｃｌｉｎＡ／ｃＤＫ２也能使Ａｘｉｎ磷酸化．Ａｘｉｎ有１０处ｃＤＫ２磷酸化位点，都定位在＿Ｂ连环蛋白结合区域，这些磷酸化位点也是ＧｓＫ一３８的作用位点．ｃｙｃｌｉｎＡ／ｃＤＫ２对ａ】【ｉｎ的磷酸化作用同样增强了ａＤｃｉｎ与８连环蛋白的结合㈨３．ＧｓＫ．３｜３和ｃＤＫ２存在一些共同的特点，它们有相似的结构，并且都催化靠近Ｐｍ的ｓｅｒ／ｎｒ磷酸化位点，这也是ａｘｉｎ能成为两种激酶的底物的原因．但是ｃｖｃｌｉｎＡ，ｃＤＫ２催化的磷酸化没有增强它对ＧｓＫ．３８的亲合性．值得注意的是，ｃｙｃｌｉｎＡ／ｃＤＫ和ｃｙｃｌｉｎＥ／ｃＤＫ复合物都能穿梭于核质之间，表明这些复合物能直接对细胞质中的ａｘｉｎ磷酸化。２０ｏ，所以ｃｖｃｌｉｎ／ＣＤＫ２这种细胞周期调节因子，通过调节ａｘｉｎ的磷酸化在ｗｎｔ信号通路中负调节Ｂ连环蛋白．３．６其它因子对ａｘｉｎ下调ｐ连环蛋白的影响突触构架分子ｓ．ｓＣＡＭ是一种含有后突触密度相关结构域ＰＤｚ（ｐｏｓｔｓｙｎａｐｔｉｃｄｅｎｓｉｔｙｄｏｍａｉｎ）、鸟苷酸激酶区域和ｗｗ区域的突触蛋白，它能与ＧｓＫ．３』３竞争性地结合在ａｘｉｎ上，与８连环蛋白、ａｘｉｎ形成复合体，因此ｓ—ｓｃＡＭ能抑制ａｘｉｎ通过ＧｓＫ．３Ｂ对｜３连环蛋白的磷酸化作用¨…．转录抑制因子Ｉ—ｎ血和含Ｉ．ｎ血区域的蛋白ＨＩｃ（ｈｕｍａｎＩ—Ｈ血ｄｏｍａｉｎ．ｃｏｎｔａｉｎｉｎｇｐｍｔｅｉｎ）也能通过它们共有的ｃ末端Ｉ—ｒ－如区域与ａＸｉｎ结合，抑制ａｘｉｎ下调Ｊ３连环蛋白¨…．４Ａｘｉｎ通过Ｗｎｔ信号途径调节的生物学效应４．１抑制体轴发育僦流突变的胚胎会产生双向体轴．爪蟾胚胎中注射ａｘｉｎ会产生严重的体轴缺陷，说明ａＸｉｎ是体轴发育抑制因子¨４。…．Ａｘｉｎ能抑制ｗｎｔ、Ｄｖｌ和ＧＳＫ一３Ｊ３诱导的二向体轴的形成，而不影响Ｂ连环蛋白和ｓｉａｍｏｉｓ诱导的二向体轴的形成‘５７｜；注射ｎｏｇｇｉｎ或显性负调节的骨形态发生蛋白受体也能导致二向体轴第４期金利华：Ａｘｉｎ在ｗｍ信号转导途径中的作用２９３的形成，但是ａＸｉｎ却不能阻断这个诱导作用．说明ａｘｉｎ调节体轴发育主要是通过抑制ｗｎｔ信号转导途径来完成的Ｈｏ．在爪蟾胚胎中注射缺失ＤＩｘ结构域的ａｘｉｎ突变体不能表现出明显的体轴抑制效果，表明ａｘｉｎ的ｃ末端ＤＩｘ结构域在该过程中起着重要作用‘川．４．２诱导细胞死亡由于８连环蛋白可通过激活癌基因表达引起细胞异常增殖，而ａｘｉｎ又可下调Ｂ连环蛋白水平，因此，ａｘｉｎ被认为是一个非常重要的肿瘤抑制因子．Ｈｓｕ等人通过转基因研究证明ａｘｉｎ的高表达可引起体内细胞凋亡ｂ“，ｓａｔｏｈ等人发现功能缺失的ａｘｉｎ突变体能使ｊ３连环蛋白稳定和积累，腺病毒转染野生型ａｘｉｎ到ａｘｉｎ或ＡＰＣ突变的癌细胞，导致８连环蛋白降解及细胞凋亡ｂ９Ｉ，都说明瓢ｉｎ是肿瘤抑制因子．４．３参与神经元的分化Ａｘｉｎ也参与神经元的分化过程．胚胎癌细胞Ｐ１９ＥＣ是一种能被视黄酸（ＲＡ）刺激分化的细胞．在未分化的Ｐ１９ＥＣ细胞中能检测到ａｘｉｎ的表达．但是，当ＲＡ诱导细胞逐渐分化为神经元细胞的过程中ａｘｉｎ的表达量明显减少．而在由ＲＡ诱导分化为内皮层细胞的过程中未见ａｘｉｎ表达水平的减少．在内皮层和早期神经元分化过程中诱导ａＸｉｎ表达，不会抑制内皮层分化，但能抑制神经元分化旧ｏ．所以ａｘｉｎ水平下降是神经元分化特有的特点，ｗｎｔ信号途径通过下调ａｘｉｎ的水平在神经元的分化过程中起着重要作用．在成神经细胞瘤Ｎ２ａ（Ｎｅｕｍ一２ａ）细胞中，ｗｎｔ信号能抑制ＧｓＫ一３ｐ的激酶作用并导致１３连环蛋白积累．锂离子处理也能起到类似的效果．锂离子和ＧｓＫ．３Ｊ３的抑制剂都能诱导Ｎ２ａ细胞突的生长，但是锂离子诱导细胞神经突的生长时Ｊ３连环蛋白的转录活性不会上升，ＧｓＫ一３１３的底物ａｘｉｎ稳定性降低．过量表达的ａＸｉｎ能抑制锂离子诱导的神经突的生长，这一过程中ＧｓＫ一３８结合区域是必需的，而ｐ连环蛋白结合区域显得不重要，表明ａＸｉｎ和ＧｓＫ一３８参与了神经细胞神经突生长的信号转导过程№“．５结语Ａｘｉｎ自从被克隆以来就成为了一个非凡的多向性构架蛋白．Ａｘｉｎ除了能与ｗｎｔ通路中的重要成员结合并参与该通路的作用以外，还能与ＪＮＫ、ｐ５３、ＴＧＦ—ｐ等多种重要信号转导途径中的多种蛋白万　方数据相互结合，因而它可能介导了ｗｎｔ通路与其它信号通路之间的功能交叉，从而在细胞命运决择和肿瘤发生的抑制方面起着关键的作用．在研究ａｘｉｎ在ｗｎｔ信号途径发挥多重功能的机理的同时，对瓤ｉｎ在不同肿瘤组织中检测突变的研究也从另一方面证实了ａＸｉｎ的抑癌功能．已有报道表明，似流１基因在肝癌ｂ９’６２州ｏ、成神经管细胞瘤旧］、结肠癌旧］、膀胱癌旧１等肿瘤组织中都存在不同频率的突变，很多突变都影响了ａｘｉｎ在ｗｎｔ信号途径中的正常调节功能，使肿瘤组织细胞中Ｂ连环蛋白产生积累．说明ａｘｉｎ作为肿瘤抑制因子，其突变导致的功能缺陷可能是导致肿瘤发生的根源之一．嬲流１基因突变的检测可能作为肿瘤的一种诊断方式．ＡＸｉｎ通过ｗｎｔ信号转导通路调节细胞增殖、凋亡等机理的研究，对探索ａｘｉｎ在各种癌症治疗方面的应用前景具有重要的指导意义．参考文献（Ｒｅｆｅｒｅｎｃｅｓ）１ＫｉｋｕｃｈｉＡ．Ｒ０ｌｅｓｏｆＡｘｉｎｉｎｔｈｅｗｎｔｓｉｇｎａｌｌｉ“ｇｐａｔｈｗａｙ．＆盯甄，，脚，１９９９，１１（１１）：７７７～７８８Ｌｕｏｗ，“ｎＳＣ．Ａ］￡ｉｎ：ｍａｓｔｅｒｓｃａⅡｂｌｄｆｏｒｍｕｌｔｉｐｌｅｓｉｇｎａｌｉＩｌｇｐａｔｈｗａｙｓ．Ⅳｅ“瑚咖口厶，２００４，１３（３）：９９—１１３Ｚｅ“ｇＬ，ＦａｇｏｔｔｏＦ，Ｚｈ舳ｇＴ，ＨｓｕＷ，ＶａｓｉｃｅｋＴＪ，ＰｅｒｒｙＷＬ３ｒｄ，【船ＪＪ，ＴｉｌｇｈｍａｎＳＭ，ＧｕｍｂｉｎｅｒＢＭ，ｃｏｓｔａｎｔｉｎｉＦ．１１ｌｅ啪ｕｓｅＦｕｓｅｄｌｏｃｕｓｅｎｃｏｄｅｓＡｘｉｎ，ｉｎｈｉｂｉｔｏｒ０ｆｔｈｅＷｎｔｓｉ印““ｇｐａｔｈｗ８ｙｔｈａｔ”ｇｔＩｌａｔｅｓｅｒＩｌｂｒｙｏｎｉｃａ］【ｉｓｆｏｒＩＩｌａｔｉｏｎ．＆ｆ２，１９９７，帅（１）：１８ｌ一１９２４ＫｉｋｕｃｈｉＡ．ＭｏｄｕｌａｔｉｏｎｏｆｗｎｔｓｉｇＩｌａｌｉ“ｇｂｙＡｘｉｎａＩｌｄＡｘｉｌ．Ｃ如。七ｆ鹏Ｇ而＂ｍ，ｋ￡ｏｒ尺。，１９９９，１０（３．４）：２５５—２６５５ＫｉｓｈｉｄａＳ，ＹａｍａＩＴｌｏｔｏＨ，ＩｋｅｄａＳ，ＫｉｓｈｉｄａＭ，ＳａｋａｍｏｔｏＩ，Ｋｏｖ啪ａＳ，ＫｉｋｕｃｈｉＡ．Ａｘｉｎ，ａｎｅｇａｔｉｖｅｒｅｇｕｌａｔｏｒｏｆｔｈｅｓｉ印ａｌｉ“ｇｐａｔｈｗａｙ，ｄｉｒｅｃｎｙｉｎｔｅｒａｃｔｓｗｉｔｈａｄｅｎｏｍａｔｏｕｓｐｏ】ｙｐｏｓｉｓｃｏｌｉａｎｄｒ。ｇｌｌｌａｔｅｓｔｈｅｓｔａｂｉｌｉｚａｔｉｏｎｏｆｂｅｔａ．ｃａｔｅｎｉｎ．ＪＢ幻ＺＣｋｍ，１９９８，２７３（１８）：１０８２３～１０８２６ＨｓｕＷ，Ｚｅ“ｇＬ，ＣｏｓｔａｎｔｉｎｉＦ．Ｉｄｅｎｔｉ６ｃａｌｉｏｎｏｆｄｏｎ西ｎｏｆＡｘｉｎｔｈａｔｂｉｎｄｓｔｈｅｓｅ血ｅ，ｔｈｒｅｏｎｉｎｅｐｒｏｔｅｉｎｐｈｏｓｐｈａｔ髂ｅ２Ａａｎｄｓｅｌｆ＿ｂｉｎｄｉｎｇｄｏＨｌａｉｎ．ＪＢｉｏｆＣｋｍ，１９９９，２７４（６）：３４３９～３４４５ｚｈａ“ｇＹ，ＱｉｕＷＪ，ＬｉｕＤＸ，ＮｅｏＳＹ，Ｈｅｘ，ＬｉｎＳＣ．ＤｉｆｆｅｒｅｎｔｉａｌｍｏｌｅｃｕｌａｒａｓｓｅｍｂｌｉｅｓｕｎｄｅｄｉｅｔｈｅｄｕａｌｆｕｎｃｔｉｏｎｏｆＡｘｉｎｉｎｍｏｄＩｌｌａｔｉ“ｇｔｈｅＷｎｔａｎｄＪＮＫｐａｔｈｗａｙｓ．ＪＢ幻ｚ（冼ｅｍ，２００１，２７６（３４）：３２１５２—３２１５９ｚｈ８ｎｇＹ，ＱｉｕＷＪ，ＣｈａｎＳＣ，ＨａｎＪ，Ｈｅｘ，ＬｉｎＳＣ．Ｃ船ｅｉｎｋｉｎａｓｅＩａｎｄｃａｓｅｉｎｋｉｎａｓｅⅡｄｉ雎ｒｅｎｔｉａｌｌｙｒｅｇＩｌｌａｔｅＡｘｉｎｆｕｎｃｔｉｏｎｉｎＷｎｔ蛐ｄＪＮＫｐａｔｈｗａｙｓ．，Ｂ“ｃ＾ｅｍ，２００２，２７７（２０）：１７７０６～１７７１２９ＩｋｅｄａＳ，ＫｉｓｈｉｄａＳ，Ｙａｍ蛐ｏｔｏＨ，ＭｕｒａｉＨ，ＫｏｙａｍａＳ，ｌ（ｉｋｕｃｈｉＡ．Ａｘｉｎ，ｎ。ｇａｔｉｖｅｒｅｇＩｌｌａｔｏｒｏｆｔｈｅＷｎｔｓｉｇＩｌａｌｉ“ｇｐａｔｈｗａｙ，ｆｂｎｍｃｏｍｐｌｅｘｗｉｔｈＧｓＫ３ｂｅｔａａｎｄｂｅｔ驴ｃａｔｅｎｉｎａＩｌｄｐｍｍｏｔｅｓＧＳＩ（３ｂｅｔａ－ｄ。ｐｅｎｄｅｎｔｐｈｏｓｐｈｏｒｙｌａｔｉｏｎｏｆｂｅｔａ—ｃａｔｅｎｉｎ．册０，，１９９８，１７（５）：１３７１一１３８４１０Ｓｃｈｗ眦一ＲｏｍｏｎｄＴ，ＡｓｂｒａｎｄＣ，ＢａｋｋｅｒｓＪ，ＫｕｈｌＭ，Ｓｃｈ跎雎ｒＨＪ，２９４中国生物化学与分子生物学报Ｊ，Ｊ，Ｗ．Ｔｈｅｂｅｔａ·２５２２卷ＨｕｅｌｓｋｅｎＢｅｈｒｅｎｓｐｍｔｅｉｎＨａｍｎｌｅ璐ｃｈＩＩｌｉｄｔｒｅｃｎｌｉｔｓＭ，ＢｉｒｃｈＩｎｅｉｅｒｋｉｎａ８ｅＩＥ１９９８，８（１０）：５７３—５８１蛐ｋｙｒｉｎｃａｔｅＩｌｉｎＩｅｐｅａｔｄｉｖｅ商ｎｃａｓｅｉｎｔｏ山ｅＤ８ｊ蛐ｉＲ，Ｆｒ够ｅｒＥ，Ｒ０ｅＴＣ，Ｐｅ盯ｌｌ【ｉｎａｓｅＬｓＭ，Ｙｅ０Ｍ，Ｇ００ｄｂａｓｉｓｆｏｒＶＭ，Ｔｈｏｍｐ∞ｎｏｆＶ，ＤａｌｅｄｅｇｒａｄａｔｉｏｎｃｏＨＩｐｌｅｘ锄ｄ∽ｔｓｉｎｂｏｔｈｃａＩｌｏｎｉｃａｌｗｍ蛐ｄＷｎｔ，Ｈ．‰ｃｔｕＩａｌｔｌｌｅｒｅｃｎｌｉｔ眦ｎｔｇｌｙｃｏｇｅｎ８ｙｌｌｔｌｌａｓｅＪＮＫ１１ｓｉｇＩｌａｌｉｎｇ．＆ＷＤｄ，２００２，１６（１６）：２０７３～２０８４Ｔ，ＣａｌｄｗｅＵＫ，Ｏ’ＫｅｅｆｅＬ，ｓｃｈｗａｒｔｚＳ，Ｖａｉｚｅｌ—Ｅ，ＴｏＩＩｌｌｉＩＩｓｏｎＡ，ＤｉＮａｒｄｏＳ．ＡⅡｕｗ３ｂｅｔａａｘｉｎ．ＡＰＣ∞柚ｆｏｌｄｃｏｍｐｌｅｘ．Ｅ＾ｆ日０Ｊ，２００３，２２ＷｅｈｒｌｉＭ，Ｄｏ“ｇ蛐ＳＯｈａｙ仰Ｄ，Ｓｃｈｅｊｔｅｒ（３）：４９４～５０１２６ｅｎｃｏｄｅｓ柚Ｓａｋ帅ａｌ【ａｔＩｌｅＣＣ，Ｗｉｕｉ枷ｓＬＴ．Ｆｕｎｃｔｉｏｎａｌｄｏｍａｉｎｓｏｆ麟ｉｎ—ｉｍｐｏｒｔ蛐ｃｅｏｆＬＤｈｅｃｅｐｔｏｒ＿ｒｅｌａｔｅｄｐｒｏｔｅｉｎｅｓｓｅＩｎｉａｌｆｏｒｗｉｎｇｌｅｓｓ８ｉ印ａｌｉｎｇ．№ｔ删，ｔｅｍｉｎ∞船船ｏｌｉｇｏｍｅｒｉｚａｔｉｏｎｄｏｎｌａｉｎ．Ｊ胁ＺｉｎＣｋｍ，１９９９，２７４２０００，４盯（６８０３）：５２７—５３０１２（２０）：１４０９０～１４０９３ＧＨＭ∞Ｊ，Ｗ朋ｇＪ，ＬｉｕＢ，Ｐ帅Ｗ，Ｆａｒｒ３ｒｄ，ｎｙｎｎＣ，Ｙｕ卸Ｈ，ｌｉｐｏｐｒｏｔｅｉｎｍｃｅｐｔ０卜２７Ｐｅ如ｒＭ，ＰｏＬ出ｓＰ．Ｗｎｔｓｉ印ａｌｉＩＩｇ１００ｋｏｕｔｓｉｄｅｔｌｌｅｏｎｃｏｇｅｎｅｓｉｓ卸ｄｅＩｌｌｂｒｙｏｇｅｎｅｓｉｓ－ａ１址ａｄａＳ，鼬ｍｅｌｒ岫ｎＤ，ＵＬ，ＷｕＤ．ｋｗ．ｄｅＩｌ８ｉｔｙｒｅｌａｔｅｄｐｒｏｔｅｉｎ一５ｂｉｎｄｓｎｕｃｌｅｕ８．＆话ｎｃｅ，２０（）ｏ，２８７（５４５８）：１６０６—１６０９Ｍ，ＨｉＵＶ，ＹｏｃｈｕｍＡ，ＶｉｒｓｈｕｐｔＩｌｅＤＭ．Ｃａｓｅｉｎｄｅ乎乜ｄ砒ｉｏｎｔｏ血ｉｎ卸ｄ喇；Ｉｌｌ８ｔｅｓｔｌｌｅｃａｎｏｎｉｃａｌＷｎｔｓｉｇｌｌａｌｉｎｇ２８ＧａｏＺＨ，Ｓ∞ＨｎｇＪＩｐａｔｈｗａｙ．＾ｆｏｆ＆肛，２００１，７（４）：８０ｌ～８０９１３ｋｉｎａｓｅｗｉｔｈｐｈ０８ｐｈｏｒｙｌａｔｅｓ趴ｄｄｅｓｔａｂｉｌｉ嬲ｓｂｅｔａ－ｃａｔｅｎｉｎＫｕ咖ｏＳ，Ｒａａｂ－ＴｒａｕｂＮ．Ｉ一Ⅲｆａｄｏｍｉｎｐｒｏｔｅｉ璐ｉｎｔｅｒａｃｔａｎｄＡｘｉｎ蛐ｄｃｏｍｐｌｅｘ．Ｐｍｃ肌“Ａ∞ｄＳｄ嬲Ａ，２００２，鲫（３）：１１８２一１１８７２９ＨｉｎｏＳ，Ｍｉｃｈｉｕｅ如ｃｔ１４ｉｔｓｒｅｇＩｌｌ砒ｉｏｎｏｆｔｈｅｗｎｔｃ－ＪｕｎＮ—ｔｅｒＩＩｌｉｎａｌｋｉＩｌａｓｅｓｉｇｎａｌｉｌｌｇＴ，Ａ钳８ｈｉ啪Ｍ，ＫｉｋｕｃｈｉＡ．Ｃａ∞ｉｎｋｉｎａ∞Ｉｉｓ船∞ｎｔｉａｌｆｏｒｅｐｓｉｌｏｎｐａｔｈｗａｙｓ．肼甜ｃｅ盯口捌，２００２，２２（１８）：６３９３～６４０５ＫａｄｏｙａＴ，ＫｉｓｈｉｄａＳ，ＦｕｋｕｉＡ，ＨｉｎｏｉＴ，Ｍｉｃｈｉｕｅｅｎｈ如ｃｅｓｔｈｅｂｉｎｄｉｎｇｏｆＤｖｌ一１Ｆ豫ｔ－１ａｎｄＷｎｔ一３ａ－Ｔ，Ａｓａｓｌｌｉ眦Ｍ，ｎｏｖｄＡｘｉｎ．ｂｉｎｄｉ“ｇ３０ｉｎｄｕｃｅｄａｃｃｕｍｕｌａｔｉｏｎｏｆ１４０６６一１４０７３ｂｅｔａ．ｃａｔｅｎｉｎ．ＪＢ“ＣＪｌｅｍ，２００３，２７８（１６）：晒ｋｕｃｈｉＡ．Ｉｎｈｉｂｉｔｉｏｎ０ｆＷｎｔｓｉｇＩｌａｌｉ“ｇｐａｔ｝１ｗａｙｂｙｐｒｏｔｅｉｎ．ＪＢｉ以Ｃｋｍ，２０（）ｏ，２７５（４７）：３７０３０一３７０３７１５ＮｉｓｈｉｄａＨｅｎｄｅ啪ｎｎｕｃｌｅａｒＢＲ，Ｆ唧ｔｔｏＦ．ｎｅｉｎ８蛐ｄ０ｆＡＰＣ彻ｄｂｅｔａ－ｃａｔｅｎｉｎＴ，Ｋ蛐ｅｋｏＦ，ＫｉｔａｇｄｗａＭ，Ｙ踮ｕｄａＨ．Ｃｈａｒａｃｔｅｒｉｚａｔｉｏｎ０ｆｔⅧ１ｓｐｏｒｔ．励佃０脚，２００２，３（９）：８３４～８３９Ｒ，ＣｌｉｆｆｅＡ，Ｂ珀ｂｌｅｔｚＴ，ＢｉｅｎｚＭ．Ｎｕｃｌｅａｒ∞ｖｅｌｍｔｍ栅ｍａｌｉａＩｌｗｈｉｃｈＳＵＭ０—１，Ｓｍｔ３一ｓｐｅｃｍｃｉｓｏｐｅｐｔｉｄ∞ｅ，ａｉｓｈｏ啪ｌｏｇＩＩｅ《ｂｅｔａ．ｃａｔｅｎｉｎ３１Ｒｏｓｉｎ－Ａｒｂｅ如ｌｄｏｆａｘ啪，卸ａｘｉｎ．ｂｉｎｄｉ“ｇｐｒｏｔｅｉｎｐＩｏｍｏｔｉｎｇｔｌｌｅＡＰＣｔｕⅡｍｒｓｕｐｐｒｅ黯ｏｒｃｏｎｔｍｌｓｂｅｔａ—ｃａｔｅｎｉｎｆｕｎｃｔｉｏｎｉｎｔ砌ｓｃｒｉｐｔｉｏｎ．ｄ哪ｄａｔｉ∞．．，尉以ｃ＾∞ｉ，２００１，２７６（４２）：３９０６０一３９０６６１６ＫａｄｏｙａＥ＾佃Ｏ．，，２０（Ｂ，２２（５）：】１０１～１１１３３２ＨｉｎｏｉＴ，Ｙａｍａ啪ｔｏＴ，Ｔａｎａｌ【ａＨ，Ｓｕ踟ｋｉＴ，ＹｕｋｉｔａＡ，ＦｕｋｕｉＡ，ＭｉｃｈｉｕｅＴ，Ｔ，Ｙａｍ舢ｔｏｏｆＨ，ＫｉｓｈｉｄａＭ，ＴａｋａｄａＳ，ＫｉｓｈｉｄａＳ，ＫｉｋｕｃｈｉＡ．ｐｒｏｄｕｃｔａｎｄａ】【ｉｎｏｆＡｓａｌｌｍｏｆＫ，Ａｓ鹊ｈｉｍａＭ，ＫｉｋｕｃｈｉＡ．ＤｅｓｕｍｏｙｌａｔｉｏｎａｃｔｉｖｉｔｙｃｏｍｐｌｅｘｆｏｒＩＩ姘ｉｏｎｆａｃｉｌｉｔａｔｅ８ａｄｅ∞眦ｔｏｕ８ｐｏｌｙｐｏｓｉｓｃｏｌｉｇｅｎｅＡｘ锄，ａｎｏｖｅｌＡｘｉｎ－ｂｉｎｄｉ“ｇｐｒｏｔｅｉｎ，ｉｓｉｎｖ０１ｖｅｄｉｎｄｏｗｎｒｅｇｌｌｌａｔｉｏｎｏｆｇＩｙｃｏｇｅｎｓｙＩＩｔｈ够ｅｋｉｎａ鸵一３ｂｅｔａ—ｄ８ｐｅｎｄｅｎｔｐｈｏｓｐｈｏｒｙｌａｔｉｏｎｂｅｔａ．ｃａｔｅｎｉｎ．肘甜Ｃ础Ｂ“，２００２，２２（１１）：３８０３—３８１９１７ＫｉｓｈｉｄａＳ，Ｙａｍａｍｏｔ０Ｈ，ＨｉｎｏＳ，ＩｋｅｄａＤＩＸＳ，ｌ（ｉｓｈｉｄａＭ，ＫｉｋｕｃｈｉＡ．３３ｂｅｔａ—ｃａｔｅｎｉｎ粕ｄｄｏｗｎ—ｒｅｇＩｌｌａｔｅｓｂｅｔａ－ｃａｔｅｎｉｎ．Ｊ曰抽ＺＣｋｍ，２０００，２７５（４４）：３４３９９—３４４０６ＫａｗａｈａｒａｄｏｍｉｎｓｏｆＤｖｌａｎｄＡｘｉｎｎｅｃｅｓｓａｒｙｆｏｒｐｍｔｅｉｎｉｍｅｒａｃｔｉｏｎｓａＩｌｄＫ，Ｍ面ｓｈｉｔａＴ．Ｔ，ＮａｋａｍｕｍＴ，ＨａｍａｄａＦ，Ｔ０ｙｏｓｈｉｍａＫ，ｃｏｌｏｒｅｃｔａｌｔｕｍｏｒｔｈｅｉｒａｂｉｌｉｔｙｒｅｇｕｌａｔｅｂｅｔａ－ｃａｔｅｎｉｎｓｔａｂｉｌｉｔｙ．胁Ｚ例Ｚ肋ｆ，１９９９，１９Ｅ，ＦａｇｏｕｏＦ，３４Ａｋｉｙ啪ａＤｏｗｎ—ｒｅｇｌｌｌａｔｉｏｎｏｆｂｅｔａ—ｃ８ｔｅｎｉｎｗｉｔｈｂｙｔｈｅ（６）：４４１４—４４２２１８ｓｕｐｐｒｅｓｓｏｒＡｐＣｒｅｑＩｌｉｒｅｓ鹊ｓｏｃｉａｔｉｏｎＡｘｉｎ锄ｄｂｅｔａ—ｃａｔｅｎｉｎ．Ｊ曰谢ＪｕｌｉｕｓＭＡ，ｓｃｈｅｌｂｅｎＢ，ＨｓｕＷ，ＦｉｔｚｐａｔｒｉｃｋＥ，Ｊｌｌｏ饥ｅｍ，２０００，２７５（１２）：８３６９～８３７４ＲｕｂｉｎｆｅｌｄＢ，ＴｉｃｅＤＡ，ＰｏｌａｋｉｓＰ．Ａｘｉｎ－ｄ。ｐｅｎｄｅｎｔｐｒｏｔｅｉｎｍｅｄｉａｔｅｄｂｙＣ０ｓｔ蛐ｔｉｎｉＦ，ＫｉｔａｊｅｗｓｋｉＪ．ＤｏＩｎａｉｎｓｏｆ戕ｉｎｉｎｔｅｒａｃｔｉｏｎａｎｄｆｕｎｃｔｉｏｎｉｎａｎｄｄｉｓｈｅｖｅｌｅｄｒｅｑＩｌｉｒｅｄｆｏｒｐｈｏｓｐｈｏｒｙｌａｔｉｏｎｃ鹊ｅｉｎｋｉｎａｓｅＩ．ｏｆｓｉ印ａｌｉｎｇ．肋ｃｋｍＢ卸＾声鼢Ｓ，Ｋｉｋｕｃｈｉ３５ｔｈｅａｄｅｎｏｍａｔｏｕ８ｐｏｌｙｐｏｓｉｓｃｏｌｉＪＣｂ肼ｎｕｎ，２０（）ｏ，２７６（３）：１１６２～１１６９１９Ｂ埘纨ｍ，２００１，”６（４２）：３９０３７—３９０４５ｓａｋ粕ａｋａｋｉｎ舾ｅＣ，ＩＪｅｏｎｇＰ，ＸｕＨｉｍｂａｙａｓｈｉＡ，ＴａｎａｋａＳ，ＮｉｓｈｉｍｕｒａＮ，Ｈａ诅Ｙ．Ｗ，ＩｉｄａＪ，ＫａｎｓａｋｕＡ，ＫｉｓｈｉｄａＬ，Ｈａ而ｓｏｎＳＤ，ＷｉｌｌｉａｍｓＬＴ．Ｃａｓｅｉｎｓｙｎ印ｔｉｃｓｅａｆｆｏｌｄｉ“ｇ啪ｌｅｃｕｌｅｉｎｔｅｒａｃｔ８ｗｉｔｈＩｅｐｓｉｌｏｎｉｎｔｈｅｓｃｉＷｎｔｐａｔｈｗａｙ：ｒｅｇＩｌｌａｔｉｏｎｏｆｂｅｔａ—ｃａｔｅｎｉｎｆｕｎｃｔｉｏｎ．“ｉｎ．ＪＭｕｒｏｃ＿Ｉｌｅｍ，２００４，如（２）：３３２—３３９２０ＫｉｍＳＩ，ＰａｒｋＣｄｅｐｅｎｄｅｎｔｋｉｎａｓｅＰｒｏｃ＾ｈ“Ａ∞ｄＥｕｓＡ，１９９９，％（２２）：１２５４８一１２５５２Ｍ，ＭａｔｓｕｕｒａＹ，Ｕｓｕｉ０ｆａｄｅｎｏｎｍｔｏｕ８ａｎｄＨ，ＫｉｋｕｃｈｉＡ．ＧＳＫ３ｂｅｔａ．ｇｅｎｅ２ＡｐｒｏｄｕｃｔＳ，ｋｅＭＳ，ＫｗｏｎＭＳ，ＪｈｏＨ，Ｓ０“ｇＷＫ．Ｃｙｃｌｉｎ—３６ＩｋｅｄａＳ，Ｋｉｓｈｉｄａ２ｒｅｇＩｌｌａｔｅｓｔｈｅｉｎｔｅｒａｃｔｉｏｎｏｆＡｘｉｎｗｉｔｈｂｅｔａ—ｃａｔｅｎｉｎ．ｄ８ｐｅｎｄｅｎｔｐｈ０８ｐｈｏｒｙｌａｔｉｏｎｐｏｌｙＰｏｓｉｓｃｏｌｉＢｉｏｃｋｍ２ｌＢ泖＾”鼢ｃｏ肼ｎ帆，２００４，３１７（２）：４７８～４８３Ｊ，Ｋｉ８ｐｅｒｔＡ，ＫｅＨｄｅｒＲ．ｂｅｔａ—ｃａｔｅｎｉｎｃ粕ｂｅｗｉｔｈ３７ｍｏｄｕｌａｔｅｄｂｙｂｅｔａ－ｃａｔｅｎｉｎｐｒｏｔｅｉ“ｐｈｏｓｐｈａｔａｓｅｃｏｍｐｌｅｘｅｄＡｂｅｄｅＨＡ，ＢａｕｅｒＡ，ＳｔａｐｐｅｒｔｉｓＡｘｉｎ．０∞曙∞ｅ，２０００，１９（４）：５３７～５４５ｔａｒｇｅｔｆｏｒｔｈｅｕｂｉｑｕｉｔｉＩｌ—ｐｍｔｅａｓｏｍｅｐａｔｈｗａｙ．Ｅ枷ＯＪ，１９９７，１６ＨａＮＣ，ＴｏｎｏｚｕｋａＴ，Ｓｔａ咖ｓＪＬ，ＣｈｏｉＨＪ，ＷｅｉｓＷＩ．Ｍｅｃｈａｎｉｓｍｏｆｉｎ（１３）：３７９７—３８０４２２ＬｉｕＣ，ＬｉＹ，ｓｅｍｅｎｏｖＸ．ＣｏｎｔｍｌｏｆＭ，ＨａＩｌＣ，ＢａｅｇＧｂｅｔａ－ｃａｔｅｎｉｎｐｈｏｓｐｈｏｒｙｌａｔｉｏｎ－ｄｅｐｅｎｄｅｎｔｂｉｎｄｉ“ｇｏｆＡｆ）ｃｂｅｔａ－ｃａｔｅｎｉｎａｎｄｉｔｓｍｌｅＨ，７ｒ粕Ｙ，ＺｌｌａｎｇＺ，“ｎｂｙｂｅｔａ－ｃａｔｅｎｉｎ３８Ｘｉ“ｇｄｅ铲ａｄａｔｉｏｎ．胁ｆＷＣ扰，２００４，１５（４）：５１ｌ～５２ｌＷ．ＣｒｙｓｔａｌｆｏｒｔｈｅＸ，Ｈｅｐｈｏｓｐｈｏｒｙｌａｔｉｏｎ／ｄｅｇｒａｄａｔｉｏｎＹ，ＣｌｅⅡｌｅｎｔｓＫ，ＫｉｍｅｌｍａｎＤ，Ｘｕｓ“ｇｇｅｓｔ８０ｆｄｕａｌ．ｋｉｎ∞ｅ２３Ｋａｒｉｍｍｅｃｈａｎｉｓｍ．例Ｚ，２００２，１０８（６）：８３７—８４７Ｔ，ｓｃｏｌｙｅｒＲ，ＩＪｅｅＳ．Ｔｈｅｂｅｔａ－ｃａｔｅｎ耐ａ］【ｉｎｃｏｍｐｌｅｘｏｆｔｈ８ＨｌｅｃｈａＩｌｉｓｍｂｅｔａ－ｃａｔｅｎｉｎＲ，ＴｓｅＧ，Ｐｕｔｔｉｗｎｔｐａ￡ｈｗａｙｊｎｔｈｅｐａｔ｝ｌｏｌｏｇｙｏｆｈｕｍｎｃａｆｌｃｅｒｓ．凡蝴，２００４，３６Ｎ，Ｒｕｂｉｒ如ｌｄＢ，Ｐ０ｌａｌ【ｉｓＰ．ｗｉｔｈＧＳＫ３ｓｉ卵ｉｆｉｃａｌｌｃｅｄｅｓｔｍｃｔｉｏｎ３９Ｃｈｏｉｃｏｍｐｌｅｘ．＆Ｍ胁，２００３，１７（２２）：２７５３～２７“ＳＪ，ＰａｒｋＹ，Ｃｏｓｔ蛐ｃｉｎｉＦ，ＪｈｏＥＨ，Ｊ００ＣＫ．Ａｄｅｎｏｍａｔｏｕ８（２）：１２０～１２８２４ＨａｒｔＭｐｏｌｙｐｏｓｉｓｃｏｌｉｉｓｄｏｗｎ’ｒｅ昏ｌｌａｔｅｄｌｏｓＳａｎｔｏｓＲ，Ａｌｂ￡ＩｎＩｂｙｔｈｅｕｂｉｑｕｉｔｉｎ－ｐｒｏｔｅａｓｏｍｅｐａｔｈｗａｙｉｎＪ，ｄｅｐｍｃｅｓｓｆ如ｉｌｉｔａｔｅｄｂｙＡ】【ｉｎ．ＪＢｉｏＺＣｋｍ，２００４，”９（４７）：４９１８８～ＤｏｗｎｒｅｇＩｌｌａｔｉｏｎｏｆｂｅｔａ—ｃａｔｅｎｉｎｔｌＩｅＡＰＣｔｕｍｏｒｂｙｈｕｍ粕Ａ五ｎ卸ｄｉｔｓ器ｓｏｃｉ撕ｏｎ４９１９８４０Ｎａｋａｍｕｒａｓｕｐｐｒｅｓｓｏｒ，ｂｅｔａ－ｃａｔｅｎｉｎａｎｄｂｅｔａ．Ｃ价口ｉ以，Ｔ，Ｈ枷ａｄａＦ，ＩｓｈｉｄａｔｅＴ，ＡｎａｉＫ，Ｋａｗａ｝ＩａｒａＫ，１研ｏｓｈｉｍａ万方数据　第４期金利华：Ａｘｉｎ在ｗｍ信号转导途径中的作用２９５Ｋ，Ａｋｉｙ姗Ｔ．Ａｘｉｎ，锄ｉｎｈｉｂｉｔｏｒｏｆｔ｝ｌｅＷｎｔｓｉｇＩｌ出“ｇｐａｔｈｗａｙ，ｉｎｔｅｍｃｔｓｗｉｔｌｌｂｅｔａ－ｃａｔｅｎｊｎ．ＧＳＫ．３ｂｅｔａ蛐ｄＡＰＣａｎｄｒｅｄｕｃｅｓｔｈｅｂｅｔａ．ｃａｔｅｎｉｎＩｅｖｅｌ．白Ⅻｃｅ凰，１９９８，３（６）：３９５～４０３４１ＷｏｎｇＣＫ，ＬｕｏＷ，ＤｅｎｇＹ，ＺｏｕＨ，ＹｅＺ，“ｎＳＣ．ＴｈｅＤＩＸＤｏｍａｉｎＰＩＤｔｅｉｎＣｏｉｌｅｄ．ｃｏｉｌ—ＤＩＸｌＩｎｈｉｂｉｔｓｃ—ＪｕｎＮ．ｔｅ肌ｉｎａｌＫｉｎ船ｅＡｃｔｉｖａｔｉｏｎｂｖＡｘｉｎ蛐ｄＤｉｓｈｅｖｅＵｅｄｔｈｒｏｕｇｌｌＤｉｓｔｉｎｃｔＭｅｃｈａｎｉｓ眦．，Ｂ“ｃ＾册，２００４，２７９（３８）：３９３６６—３９３７３４２ＳｈｉｏｍｉＫ，ＵｃｈｉｄａＨ，Ｋｅｉｎｏ－Ｍ鹊ｕＫ，Ｍ鼬ｕＭ．Ｃｃｄｌ，ａｎｏｖｄｐｒｏｔｅｉｎｗｉｔｈＤⅨｄｏｍ越ｎ，ｉｓｐ帼ｉｔｉｖｅｑ—ａｔｏｒｉｎｔｈｅｗｎｔｓｉｇ【ｌａｌｉｎｇｄＩＩｒｉｎｇｚｅｂ础ｓｈｎｅｕｒａｌｐａｔｔｅｍｉ“ｇ．Ｃｍ曰埘，２００３，１３（１）：７３—７７４３ｓｈｉｏＩＩＩｉＫ，ＫａｎｅｍｏｔｏＭ，Ｋｅｉｎｏ－Ｍ鹊ｕＫ，ＹｏｓｈｉｄａＳ，ＳｏｍａＫ，Ｍ娼ｕＭ．Ｉｄｅ眦ｉｆｉｃａｔｉｏｎａｎｄｄｉｆｆｅ陀“ａｌｅｘｐｒｅｓｓｉｏｎｏｆｍＩｌｌｔｉｐｌｅｉ８０ｆｏｍ峙ｏｆｍｏｕｓｅｃｏｉｌｅｄ．ｃｏｉｌ·ＤＩｘｌ（ｃｃｄｌ），ａｐｏｓｉｔｉｖｅｒｅｇＩｌｌａｔｏｒｏｆｗｎｔｓｉ刚ｉ“ｇ．Ｂｒ击ⅡＪ０懿肘甜Ｂｒ０讯Ｒ黜，２００５，１３５（１－２）：１６９～１８０４４ｃ彻ｇＦ，Ｖ８瑚ｕｓＨ．Ｎｕｃｌｅ妒。ｙ￡ｏｐｌ鼬商ｃｓｈｕ址ｈｎｇｏｆ心ｎ地ｇｌＪｌａ鼢ｓｕｂｃｅＵＩｌｌ盯ｌｏｃａｌｉｚａｔｉｏｎｏｆｂｅｔａ－ｃａｔｅｎｉｎ．Ｐｒｏｃ＾ｋＺＡｃ甜ｓｃｉＨｓＡ，２００４，ｌＯｌ（９）：２８８２～２８８７４５ｗｉｅｃｈｅ船Ｎ，ＨｅｉＩｌｌｅＫ，ＥｒｌｇｌｍｅｉｅｒＬ，ＳｃｈｏｌＩｌＡ，ＦａｇｏｔｔｏＦ．Ｎｕｃｌｅｏ－ｃｙｔｏｐｌ∞ｍｉｃｓｈｕｔｄｉ“ｇｏｆＡｘｉｎ，ａｎｅｇａｔｉｖｅｒｅｇＩＩｌ砒ｏｒ０ｆｔｈｅｗｎｔ—ｂｅｔａ－ｃａｔｅｎｉｎＰａｔｈｗａｙ．．，Ｂｉ甜Ｃｋｍ，２００４，２７９（７）：５２６３—５２６７４６ＷｊｅｃｈｅｎｓＮ，ＦａｇｏｔｔｏＦ．ＣＲＭｌ·卸ｄＲ蛐－ｊｎｄ印ｅｎｄ棚ｔｎｕｃｌｅａｒ麟ｐｏｎｏｆｂｅｔａ－ｃａｔｅｎｉｎ．仇ｒｒＢ“，２００１，１ｌ（１）：１８一”４７Ｃｌｉ舱Ａ，Ｈ鲫ａｄａＦ，Ｂｉｅ眦Ｍ．ＡｍｌｅｏｆＤｉｓｈｅｖｅｌｌｅｄｉｎｒｅｌｏｃａｔｉｎｇＡｘｉｎｔｈｅｐｌ船ｍｍｅｍｂｍｎｅｄｕｒｉｎｇｗｉｎｄｅｓｓ８ｉ印ａｌｉＩｌｇ．ｃｌ上丌。舶ｚ，２００３，１３（１１）：９６０一９６６４８Ｔ０１ｗｉＩｌｓｋｉＮＳ，ＷｅｈｒｌｉＭ，ＲｉｖｅｓＡ，ＥｒｄｅｒＩｉｚＮ，ＤｉＮａｒｄｏＳ，ＷｉｅｓｃｈｕｓＥ．ｗｇ，ｗｎｔｓｉｇＭｌｂｅｔｍ璐ｍｉｔｔｅｄｔｈｒｏｕｇｌｌａ咖ｗ，ＬＲＰ５，６ａＩｌｄＡｘｉｎｉｎｄｅｐｅｎｄｅｎｔｌｙｏｆＺｗ３，Ｇｓｋ３ｂｅｔａａｃｄｖｉｔｙ．踟ｃｅ２Ｚ，２００３，４（３）：４０７～４１８４９ＳｃｈｗｅｉｚｅｒＬ，Ｖ删ｕｓＨ．ｗｎ“ｗｉｎｇｌｅ蟠ｓｉｇＩｌａｌｉｎｇｔｈｍｕｇｈｂｅｔａ－ｃａｔｅｌｌｉｎｒｅｑｕｉｒｅｓｔｈｅｆｕｎｃｔｉｏｎｏｆｂｏｔｈＬＲＰ，Ａｒｒｏｗａｎｄ抽踞ｌｅｄｃｌ鹊ｓｅｓｏｆｒｅｃｅｐｔｏｒｓ．Ｂ肼ＣＣｅｆｆＢ幻Ｚ，２００３，４：４５０ＨｅＸ，ＳｅｍｅｎｏｖＭ，ＴａｍｉＫ，Ｚｅ“ｇＸ．ＬＤＬｒｅｅｅｐｔｏｒ．ｒｅｌａ砌ｐｒｏｔｅｉｎｓ５ａｎｄ６ｉｎＷｎｔ，ｂｅｔａ－ｃａｔｅｎｉｎｓｉｇＩｌａｌｉ“ｇ：ａⅡＤｗｓｐｏｉｎｔｔｈｅｗａｙ．Ｄ吼℃ｆｏｐｍｅ眦，２００４，１３１（８）：１６６３～１６７７５１Ｈａ眦ｄａＦ，Ｔｏｍｏｙ咖Ｙ，Ｔ出ｎｓｕＹ，Ｎａｌ【锄ｕｍＭ，ＮａｇａｊＳ，ＳｕｚｕｋｉＡ，ＦｕｊｉｔａＦ，ＳｈｉｂｕｙａＨ，ＴｏｙｏｓｈｉｍａＫ，ＵｅｎｏＮ，ＡｋｉｙａｍａＴ．Ｎ８９砒ｉｖｅｒｅｇｕｌａｔｉｏｎｏｆｗｉｎｇｌｅ８ｓｓｉｇＩｌａｌｉ“ｇｂｙＤ—ａ）【ｉｎ，ａＤｒ０５叩＾以Ⅱｈｏｍｏｌｏｇｏｆａ］【ｉｎ．Ｓｃｊ！ｅ，ｌｃｅ，１９９９，２ｓ３（５４０８）：１７３９一１７４２５２Ｙａｍａ咖ｔｏＨ，ＫｉｓｈｉｄａＳ，ＫｉｓｈｉｄａＭ，ＩｋｅｄａＳ，ＴａｋａｄａＳ，ＫｉｋｕｃｈｉＡ．Ｐｈｏｓｐｈｏｒｙｌａｔｉｏｎｏｆ缸ｉｎ，ａｗｎｔｓｉ印ａｌｎｅｇａｔｉｖｅｒｅｇＩｌｌａｔｏｒ，ｂｙｇｌｙｃｏｇｅｎ８ｙｎｔｈ∞ｅｋｉｎ∞ｅ－３ｂｅｔａｒｅｇｕｌａｔｅｓｉｔｓｓｔ８ｂｉｌｉｔｙ．ＪＢｉｏｆ‰ｍ，１９９９，２７４（１６）：１０６８１—１０６８４５３Ｔ０１ｗｉｎｓｋｉＮＳ，Ｗｉｅｓｃｈａｕ８Ｅ．Ｒｅｔｌｌｉｎｋｉ“ｇＷｎｔｓｉｇＩｌａｌｉ“ｇ．ｍ础＆删，２００４，２０（４）：１７７一１８ｌ５４ＦｕｋｕｉＡ，ＫｉｓｈｉｄａＳ，ＫｉｋｕｃｈｉＡ，Ａｓ鹊ｈｉｍａＭ．ＥｆｆｅｃｔｓｏｆＡ）ｃｉｎｄｏｍａｉｎｓ８）【ｉｓｆｏｎｎａｔｉｏｎｉｎｘｅｎｏｐｕｓｅＩＩｌｂｒｙｏｓ．Ｄ删‰帆Ｄ咖ｒ，万　方数据２０００，４２（５）：４８９～４９８５５ＩｔｏｈＫ，ＫｍｐｎｉｋＶＥ，ＳｏｋｏｌＳＹ．ＡｘｉｓｄｅｔｅｍｉｎａｔｉｏｎｉｎＸｅｎｏｐｕｓｉｎｖｏｌｖｅｓｂｉｏｃｈｅＩＩｌｉｃｄｉｎｔｅ强ｃｔｉｏｎｓｏｆａ】ｃｉｎ，ｇｌｙｃｏｇｅ“ｓｙｎｔｈａｓｅｋｉｎａｓｅ３蛐ｄｂｅｔａ．ｃａｔｅｎｉｎ．ＣｍＢ埘，１９９８，８（１０）：５９ｌ～５９４５６Ｋｏｆ如ｎＭ，ⅪｅｉｎＰ，ｚｈ肌ｇＦ，Ｈ０ｕｓｔｏｎＤｗ，ｓｃｈａｉｂｋＫ，ＷｙｌｉｅＣ，Ｈｅ鹊哪Ｊ．７ｒｈｅｒｏｌｅｏｆＩＩ埘ｅⅡｌａｌ缸ｉｎｉｎｐａｔｔｅｍｉ“ｇｔｌｌｅＸｅｎ叩ｕｓｅｎＩｂｒｙｏ．踟Ｂ捌，２００ｌ，２３７（１）：１８３—２０１．５７Ｂ咖∞Ｍ，Ｇ０ｍｐｅｒｔｓＭ，Ｓｕ咖ｙＬ，Ｍ００ｎＲＴ，ｌ（ｉ啪ｌ咖Ｄ．Ａｂｅｔａ－ｃａｔｅＩｌｉＩｌ／ｘＴｃｆ－３ｃｏｍｐｌｅｘｂｉｎｄｓｔｈｅｓｉ咖ｉ８ｐｍｍｏｔｅｒｒｅｇｕｌａｔｅｄｏ瑙ａｉａ】【ｉｓｓｐｅｃｉｆｉｃａｔｉｏｎｉｎＸｅｎｏｐｕｓ．＆ｒⅫ肋，１９９７，ｌｌ（１８）：２３５９～２３７０５８Ｈ鲫ｗ，ｓｈａｋｙａＲ，Ｃｏｓｔａ以ｎｉＦ．Ｉｍｐａｉｒｅｄｍａｍ嘶Ｌｒｙｄａｎｄ蛐ｄｌｙｍｐｈｏｉｄｄｅｖｅｌｏｐⅡｌｅｎｔｃ肌ｓｅｄｂｙｉｎｄｕｃｉｂｌｅｅｘｐｒｅｓｓｉｏｎｏｆ心ｎｉｎｔｍｓｇｅｎｉｃＩＩｌｉｃｅ．．，＆雎Ｂ洲，２００ｌ，１５５（６）：１０５５～１０６４５９ＳａｔｏｈＳ，Ｄａｉ８０Ｙ，ＦｕｒｕｋａｗａＹ，ＫａｔｏＴ，ＭｉｗａＮ，Ｎｉ８ｈｉｗａｋｉＴ，Ｋａｗ鼬０ｅＴ，Ｉｓｈｉｇｕｒ０Ｈ，Ｆ坤ｔａＭ，Ｔｏｋｉ加Ｔ，ＳａｓａｋｊＹ，Ｉｍ∞ｋａＳ，ＭｕｒａｔａＭ，Ｓｈｉ眦ｎｏＴ，Ｙ砌∞ｋａＹ，Ｎ８ｋ咖ｕｍＹ．ＡＸＩＮｌｍｕｔａｔｉｏｎｓｉｎｈｅｐａｔＩ）ｃｅｕｕｌ盯ｃａｒｃｉｎｏ啷，锄ｄｇｒｏｗｔｌｌｓｕｐｐｒｅ鹪ｉｏｎｉｎｃｅｌｌｓｂｙｖｉｎｌｓ．ｒｒｌｅｄｉａｔｅｄｔｍｎｄｆｅｒｏｆＡｘＩＮｌ．＾协＆恻，２０００，２４（３）：２４５—２５０６０ＬｙｕＪ，Ｃｏｓｔ明ｔｉｎｉＦ，ＪｈｏＥＨ，ＪｏｏＣＫ．ＥｃｔｏｐｉｃｅｘｐｒｅｓｓｉｏｎｏｆＡｘｉｎｂｌｏｃｋｓｎｅｕｒｏｎａｌｄｉ髓Ｉ－ｅｎｎａｌｉｏｎ０ｆｅｍｂｒｙｏｎｊｃｃａｒ：ｃｊ肿ⅡｍＰ１９ｃｅｕｓ．＿，Ｂ埘Ｃｋｍ，２００３，２７８（１５）：１３４８７～１３４９５６１０珈ｅＭＨ，Ｇｉ肌ｎｉｎｉＡＬ，Ｖｉ啪ｃｏＭＤ，蛐ｄＫｙｐｔａＲＭ．Ｇｌｙｃｏｇｅｎｓｙｎｔｌｌａｓｅｋｉｎａ８ｅ一３锄ｄＡｘｉｎｆｕｎｃｔｉｏｎｉｎｂｅｔａ—ｃａｔｅｎｉｎ．ｉｎｄｅｐｅｎｄｅｎｔｐａｔｈｗａｙｔｈａｔｒｅｇｌｌｌａｔｅｓｎｅｕｒｉｔｅｏｕｔｇｍ砒ｈｉｎｎｅｕｍｂｌ够ｔｏ啪ｃｅｌｌｓ．肘以例ｆ＾ｋⅡｒ邯ｄ，２００３，２４（３）：６７３～６８６６２ＩｓｈｉｚａｋｉＹ，ＩｋｅｄａＳ，ＦｕｊｉｍｏｒｉＭ，ＳｈｉｎｄｚｕＹ，Ｋｕｒｉｈ锄Ｔ，Ｉｔ棚ｏｔ０Ｔ，ＫｉｋｕｃｈｉＡ，Ｏｋａｊｉ呦Ｍ，Ａｓａ｝Ｉ啪Ｔ．Ｉｍｍｕｎｏｈｉｓｔｏｃｈｅｍｉｃａｌ８ｎａｌｙｓｉｓ明ｄｍｕｔａｔｉｏｎ８ｌ蚰ａｌｙｓｅｓｏｆｂｅｔａ－ｃａｔｅｎｉｎ，ＡｘｉｎｆａＩＩＩｉｌｙａｎｄＡＰＣｇｅ眦ｓｉｎｈｅｐａｔｏｃｅｌｌｕｌａｒｃａｒｃｉｎｏｍ∞．加Ｊ０Ｍ￡，２００４，２４（５）：１０７７～１０８３６３ＭｉａｏＪ，ＫｕｓａｆｕｋａＴ，ＵｄａｔｓｕＹ，０ｋａｄａＡ．Ｓｅ口ｕｅｎｃｅｖａｒｉ蛐ｔｓ０ｆｔｈｅＡｘｉ“ｇｅｎｅｉｎｈｅｐ砒ｏｂｌ鹊ｔｏ咖．＾卸Ⅲ甜胍，２００３，２５（２）：１７４一１７９６４Ｔ柚ｉｇＩｌｃｈｉＫ，ＲｏｂｅｒｔｓＬＲ，ＡｄｅｒｃａＩＮ，Ｄｏｎｇｘ，ＱｉａｎＣ，ＭｕｒｐｈｙＬＭ，ＮａｇｏｍｅｙＤＭ，Ｂｕ。ｇａｒｔＬＪ，Ｒ０ｃｈｅＰＣ，ＳＩＩｌｉｔｈＤＩ，ＲｏｓｓＪＡ，“ｕＷ．ＭｕｔａｔｉｏｒＬａｌｓｐｅｃｔｎｌｍｏｆｂｅｔａ＿ｃａｔｅｎｉｎ，ＡＸＩＮｌ，ａｎｄＡＸＩＮ２ｉｎｈｅｐａｔｏｃｅＵｕｌａｒｃａｒｃｉｎｏｍ粕ａｎｄｈ８ｐａｔｏｂｌ鹊ｔｏｍａｓ．０聊９９ｅ聊，２００２，２１（３１）：４８６３～４８７１６５ＤａｌｌｎｌｅｎＲＰ，ＫｏｃｈＡ，Ｄｅｎｋｈ叫ｓＤ，ＴｏｎｎＪＣ，ＳｏｒｅｎｓｅｎＮ，ＢｅｒｔｈｏｌｄＦ，ＢｅｈｒｅｎｓＪ，ＢｉｒｃｈｍｅｉｅｒＷ，ＷｉｅｓｔｌｅｒＯＤ，ＰｉｅｔｓｃｈＴ．ＤｅｌｅｔｉｏｎｓｏｆＡｘＩＮｌ，ｃｏｍｐｏｎｅｎｔｏｆｔｈｅｗＮＴ，ｗｉｎｄｅｓｓＰａｔｈｗａｙ，ｉｎｓｐｏｒａｄｉｃＭｅｄｕｌｌｏｂｌａｓｔｏｍａｓ．Ｃ口，ｌｃｅｒ如ｓ，２００１，６ｌ（１９）：７０３９～７０４３ＪｉｎＬＨ，Ｓｈａ０ＱＪ，Ｌｕｏｗ，ＹｅｚＹ，“Ｑ，“ｎｓｃ．Ｄｅｔｅｃｔｉｏｎ０ｆ耐ｎｔｍｕｔａｔｉｏｎｓ“ｔｈｅＡｘｉｎｌｇｅｎｅｉｎｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒｓ．胁Ｊ％，脚’，２００３，１０７（５）：６９６—６９９Ｄ舳Ｔ，Ｋ鹊ｈｉｍａＫ，Ｋａｌ【ｕＮ，ＳｕｚｕｋｉＭ，ＹｏｋｏｙａｍａＳ．Ｍｕｔａｔｉｏｎｓｉｎｃｏｍｐｏｎｅｎｔｓ“ｔｌｌｅＷｎｔｓｉｇＩｌａｌｉｎｇｐａｔｈｗａｙｉｎａｄｅｎｏｉｄｃｙ８ｔｉｃｃａＩ℃ｉｎｏｍａ．胁ｄ砌＿ＩｌＤＺ，２００４，１７（１２）：１４７５～１４８２６６６７Axin在Wnt信号转导途径中的作用

作者：作者单位：刊名：英文刊名：年，卷(期)：被引用次数：

金利华， 李勤喜， 叶志云， JIN Li-Hu， LI Qin-Xi， YE Zhi-Yun

金利华,JIN Li-Hu(厦门大学生物医学工程研究中心,厦门,361005)， 李勤喜,叶志云,LIQin-Xi,YE Zhi-Yun(厦门大学生命科学学院,厦门,361005)中国生物化学与分子生物学报

CHINESE JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY2006，22(4)0次

1.Kikuchi A Roles of Axin in the Wnt signalling pathway 1999(11)

2.Luo W.Lin S C Axin:a master scaffold for multiple signaling pathways 2004(03)

3.Zeng L.Fagotto F.Zhang T.Hsu W Vasicek T J Perry W L 3rd Lee J J Tilghman S M Gumbiner B MCostantini F The mouse Fused locus encodes Axin,an inhibitor of the Wnt signaling pathway thatregulates embryonic axis formation 1997(01)

4.Kikuchi A Modulation of Wnt signaling by Axin and Axil 1999(3-4)

5.Kishida S.Yamamoto H.Ikeda S.Kishida M Sakamoto I Koyama S Kikuchi A Axin,a negative regulator ofthe wnt signaling pathway,directly interacts with adenomatous polyposis coli and regulates thestabilization of beta-catenin 1998(18)

6.Hsu W.Zeng L.Costantini F Identification of a domain of Axin that binds to the serine/threonineprotein phosphatase 2A and a self-binding domain 1999(06)

7.Zhang Y.Qiu W J.Liu D X.Nco S Y He X Lin S C Differential molecular assemblies underlie the dualfunction of Axin in modulating the Wnt and JNK pathways 2001(34)

8.Zhang Y.Qiu W J.Chan S C.Han J He X Lin S C Casein kinase I and casein kinase Ⅱ differentiallyregulate Axin function in Wnt and JNK pathways 2002(20)

9.Ikeda S.Kishida S.Yamamoto H.Murai H Koyama S Kikuchi A Axin,a negative regulator of the Wntsignaling pathway,forms a complex with GSK3beta and beta-catenin and promotes GSK3betadependentphosphorylation of beta-catenin 1998(05)

10.Schwarz-Romond T.Asbrand C.Bakkers J.Kuhl M Schaeffer H J Huelsken J Behrens J Hammerschmidt MBirchmeier W The ankyrin repeat protein diversin recruits casein kinase Iε to the betacatenindegradation complex and acts in both canonical Wnt and Wnt/JNK signaling 2002(16)

11.Wehrli M.Dougan S T.Caldwell K.O' Keefe L Schwartz S VaizelOhayon D Schejter E Tomlinson ADiNardo S Arrow encodes an LDL-receptor-related protein essential for Wingless signaling 2000(6803)12.Mao J.Wang J.Liu B.Pan W Farr G H 3rd Flynn C Yuan H Takada S Kimelman D Li L Wu D Low-densitylipoprotein receptorrelated protein-5 binds to Axin and regulates the canonical Wnt signalingpathway 2001(04)

13.Kusano S.Ranb-Traub N I-mfa domain proteins interact with Axin and affect its regulation of theWnt and c-Jun N-terminal kinase signaling pathways 2002(18)

14.Kadoya T.Kishida S.Fukui A.Hinoi T Michiue T Asashima M Kikuchi A Inhibition of Wnt signalingpathway by a novel Axin-binding protein 2000(47)

15.Nishida T.Kaneko F.Kitagawa M.Yasuda H Characterization of a novel mammalian SUMO-1/Smt3-specificisopeptidase,a homologue of rat axam,which is an axin-binding protein promoting beta-catenindegradation 2001(42)

16.Kadoya T.Yamamoto H.Suzuki T.Yukita A Fukui A Michiue T Asabara T Tanaka K Asashima M Kikuchi A Desumoylation activity of Axam,a novel Axin-binding protein,is involved in downregulation of beta-catenin 2002(11)

17.Kishida S.Yamamoto H.Hino S.Ikeda S Kishida M Kikuehi A DIX domains of Dvl and Axin are necessaryfor protein interactions and their ability to regulate beta-catenin stability 1999(06)

18.Julius M A.Schelbert B.Hsu W.Fitzpatrick E Jho E Fagotto F Costantini F Kitajewski J Domains ofaxin and disheveled required for interaction and function in wnt signaling 2000(03)19.Hirabayashi S.Nishimura W.Iida J.Kansaku A Kishida S Kikuchi A Tanaka N Ham Y Synapticscaffolding molecule interacts with axin 2004(02)

20.Kim S I.Park C S.Lee M S.Kwon M S Jho E H Song W K Cyclindependent kinase 2 regulates theinteraction of Axin with beta-catenin 2004(02)

21.Aberle H A.Bauer A.Stappert J.Kispert A Kemler R beta-catenin is a target for the ubiquitin-proteasome pathway 1997(13)

22.Liu C.Li Y.Semenov M.Han C Baeg G H Tan Y Zhang Z Lin X He X Control of beta-cateninphosphorylation/degradation by a dual-kinase mechanism 2002(06)

23.Karim R.Tse G.Putti T.Scolyer R Lee S The significance of the Wnt pathway in the pathology ofhuman cancers 2004(02)

24.Hart M J.de los Santos R.Albert I N.Rubinfeld B Polakis P Downregulation of beta-catenin by humanAxin and its association with the APC tumor suppressor,beta-catenin and GSK3 beta 1998(10)25.Dajani R.Fraser E.Roe S M.Yeo M Good V M Thompson V Dale T C Pearl L H Structural basis forrecruitment of glycogen synthase kinase 3beta to the axin-APC acaffold complex 2003(03)26.Sakanaka C.Williams L T Functional domains of axin-importance of the C terminus as anoligomerization domain 1999(20)

27.Peifer M.Polakis P Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus2000(5458)

28.Gao Z H.Seeling J M.Hill V.Yochum A Virshup D M Casein kinase I phosphorylates and destabilizesthe beta-catenin degradation complex 2002(03)

29.Hino S.Michiue T.Asashima M.Kikuchi A Casein kinase I epsilon enhances the binding of Dvl-1 toFrat-1 and is essential for Wnt-3a-induced accumulation of beta-catenin 2003(16)

30.Henderson B R.Fagotto F The ins and outs of APC and beta-catenin nuclear transport 2002(09)31.Rosin-Arbesfeld R.Cliffe A.Brabletz T.Bienz M Nuclear export of the APC tumor suppressor controlsbeta-catenin function in transcription 2003(05)

32.Hinoi T.Yamamoto H.Kishida M.Takada S Kishida S Kikuchi A Complex formation of adenomatouspolyposis coli gene product and axin facilitates glycogen synthase kinase-3 beta-dependentphosphorylation of beta-catenin and down-regulates beta-catenin 2000(44)

33.Kawahara K.Morishita T.Nakamura T.Hamada F Toyoshima K Akiyama T Down-regulation of beta-cateninby the colorectal tumor suppressor APC requires association with Axin and beta-catenin 2000(12)34.Rubinfeld B.Tice D A.Polakis P Axin-dependent phosphorylation of the adenomatous polyposis coliprotein mediated by casein kinase I 2001(42)

35.Sakanaka C.Leong P.Xu L.Harrison S D Williams L T Casein kinase Iepsilon in the Wntpathway:regulation of beta-catenin function 1999(22)

36.Ikeda S.Kishida M.Matsuura Y.Usui H Kikuchi A GSK3beta-dependent phosphorylation of adenomatouspolyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexedwith Axin 2000(04)

37.Ha N C.Tonozuka T.Stamos J L.Choi H J Weis W I Mechanism of phosphorylation-dependent binding ofAPC to beta-catenin and its role in beta-catenin degradation 2004(04)

38.Xing Y.Clements W K.Kimelman D.Xu W Crystal structure of a beta-catenin/axin complex suggests amechanism for the beta-catenin destruction complex 2003(22)

39.Choi J.Park S Y.Costantini F.Jho E H Joo C K Adenomatous polyposis coli is down-regulated by theubiquitin-proteasome pathway in a process facilitated by Axin 2004(47)

40.Nakamura T.Hamada F.Ishidate T.Anai K Kawahara K Toyoshima K Akiyama T Axin,an inhibitor of theWnt signaling pathway,interacts with beta-catenin,GSK-3beta and APC and reduces the betacateninlevel 1998(06)

41.Wong C K.LuoW.Deng Y.ZouH YeZ LinSC The DIX Domain Protein Coiled-coil-DIX1 Inhibits c-Jun N-terminal Kinase Activation by Axin and Dishevelled through Distinct Mechanisms 2004(38)42.Shiomi K.Uchida H.Keino-Masu K.Masu M Ccd1,a novel protein with a DIX domain,is a positiveregulator in the Wnt signaling during zebrafish neural patterning 2003(01)

43.Shiomi K.Kanemoto M.Keino-Masu K.Yoshida S Soma K Masu M Identification and differentialexpression of multiple isoforms of mouse Coiled-coil-DIX1 (Ccd1),a positive regulator of Wntsignaling 2005(1-2)

44.Cong F.Varmus H Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin 2004(09)

45.Wiecbens N.Heinle K.Englmeier L.Schohl A Fagotto F Nucleocytoplasmic shuttling of Axin,a negativeregulator of the Wnt-betacatenin Pathway 2004(07)

46.Wiechens N.Fagotto F CRM1-and Ran-independent nuclear export of beta-catenin 2001(01)

47.Cliffe A.Hamada F.Bienz M A role of Dishevelled in relocating Axin to the plasma membrane duringwingless signaling 2003(11)

48.Tolwinski N S.Wehrli M.Rives A.Erdeniz N DiNardo S Wieschaus E Wg/Wnt signal can be transmittedthrough arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity 2003(03)

49.Schweizer L.Varmus H Wnt/Wingless signaling through beta-catenin requires the function of bothLRP/Arrow and frizzled classes of receptors 2003

50.He X.Semenov M.Tamai K.Zeng X LDL receptor-related proteins 5 and 6 in Wnt/beta-cateninsignaling:arrows point the way 2004(08)

51.Hamada F.Tomoyasu Y.Takatsu Y.Nakamura M Nagai S Suzuki A Fujita F Shibuya H Toyoshima K Ueno NAkiyama T Negative regulation of Wingless signaling by D-axin,a Drosophila homolog of axin1999(5408)

52.Yamamoto H.Kishida S.Kishida M.Ikeda S Takada S Kikuchi A Phosphorylation of axin,a Wnt signalnegative regulator,by glycogen synthase kinase-3beta regulates its stability 1999(16)53.Tolwinski N S.Wieschaus E Rethinking Wnt signaling 2004(04)

54.Fukui A.Kishida S.Kikuchi A.Asashima M Effects of rat Axin domains on axis formation in Xenopusembryos 2000(05)

55.Itoh K.Krupnik V E.Sokol S Y Axis determination in Xenopus involves biochemical interactions ofaxin,glycogen synthase kinase 3 and beta-catenin 1998(10)

56.Kofron M.Klein P.Zhang F.Houston D W, Schaible K, Wylie C, Heasman J The role of maternal axin inpatterning the Xenopus embryo 2001(01)

57.Brannon M.Gomperts M.Sumoy L.Moon R T Kimelman D A beta-catenin/XTcf-3 complex binds to thesiamois promoter to regulate dorsal axis specification in Xenopus 1997(18)

58.Hsu W.Shakya R.Costantini F Impaired mammary gland and lymphoid development caused by inducibleexpression of Axin in transgenic mice 2001(06)

59.Satoh S.Daigo Y.Furukawa Y.Kato T Miwa N Nishiwaki T Kawasoe T Ishiguro H Fujita M Tokino TSasaki Y Imaoka S Murata M Shimano T Yamaoka Y Nakamura Y AXIN1 mutations in hepatocellularcarcinomas,and growth suppression in cancer cells by virus-mediated trandfer of AXIN1 2000(03)60.Lyu J.Costantini F.Jho E H.Joo C K Ectopic expression of Axin blocks neuronal differentiation ofembryonic carcinoma P19 cells 2003(15)

61.Orme M H.Giannini A L.Vivanco M D.Kypta R M Glycogen synthase kinase-3 and Axin function in abeta-catenin-independent pathway that regulates neurite outgrowth in neuroblastoma cells 2003(03)62.Ishizaki Y.Ikeda S.Fujimori M.Shimizu Y Kurihara T Itamoto T Kikuchi A Okajima M Asahara T Immunohistochemical analysis and mutational analyses of beta-catenin,Axin family and APC genes inhepatocellular carcinomas 2004(05)

63.Miao J.Kusafuka T.Udatsu Y.Okada A Sequence variants of the Axin gene in hepatoblastoma 2003(02).Taniguchi K.Roberts L R.Aderca I N.Dong X Qian C Murphy L M Nagorney D M Burgart L J Roche P CSmith D I Ross J A Liu W Mutational spectrum of beta-catenin,AXIN1,and AXIN2 in hepatocellularcarcinomas and hepatoblastomas 2002(31)

65.Dahmen R P.Koch A.Denkhaus D.Tonn J C Sorensen N Berthold F Behrens J Birchmeier W Wiestler O DPietsch T Deletions of AXIN1,a Component of the WNT/wingless Pathway,in Sporadic Medulloblastomas2001(19)

66.Jin L H.ShaoQJ.LuoW.YeZY LiQ LinSC Detection ofpoint mutations of the Axinl gene in colorectalcancers 2003(05)

67.Dan T.Kashima K.Kaku N.Suzuki M Yokoyama S Mutations in components of the Wnt signaling pathwayin adenoid cystic carcinoma 2004(12)

1.外文期刊 Schwarz-Romond. T.Metcalfe. C.Bienz. M Dynamic recruitment of axin by Dishevelled proteinassemblies

Dishevelled (Dvl) proteins are cytoplasmic components of the Wnt signalling pathway, which controls numerous cell fate decisionsduring animal development. During Wnt signalling, Dvl binds to the intracellular domain of the frizzled transmembrane receptors, andalso to axin to block its activity, which results in the activation of beta-catenin and, consequently, in a transcriptional switch.We have previously reported that the DIX domain of mammalian Dvl2 allows it to form dynamic protein assemblies. Here, we show thatthese Dvl2 assemblies recruit axin, and also casein kinase I epsilon. Using photobleaching experiments of GFP- tagged Dvl2 and axinto study the dynamics of their interaction, we found that the recruitment of axin- GFP by Dvl2 assemblies is accompanied by a

striking acceleration of the dynamic properties of axin-GFP. We also show that the interaction between Dvl2 and axin remains highlydynamic even after Wnt- induced relocation to the plasma membrane. We discuss how the recruitment of casein kinase I epsilon by Dvl2assemblies might impact on the recruitment of axin to the plasma membrane during Wnt signalling.

2.外文期刊 Cselenyi. CS.Jernigan. KK.Tahinci. E.Thorne. CA.Lee. LA.Lee. E LRP6 transduces a

canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of beta-catenin

Wnt/beta-catenin signaling controls various cell fates in metazoan development and is misregulated in several cancers anddevelopmental disorders. Binding of a Wnt ligand to,its transmembrane coreceptors inhibits phosphorylation and degradation of thetranscriptional coactivator beta-catenin, which then translocates to the nucleus to regulate target gene expression. To understandhow Writ signaling prevents beta-catenin degradation, we focused on the Writ coreceptor low-density lipoprotein receptor-related

protein 6 (LRP6), which is required for signal transduction and is sufficient to activate Writ signaling when overexpressed. LRP6 hasbeen proposed to stabilize beta-catenin by stimulating degradation of Axin, a scaffold protein required for p-catenin degradation. Incertain systems, however, Wnt-mediated Axin turnover is not detected until after p-catenin has been stabilized. Thus, LRP6 may alsosignal through a mechanism distinct from Axin degradation. To establish a biochemically tractable system to test this hypothesis, weexpressed and purified the LRP6 intracellular domain from bacteria and show that it promotes beta-catenin stabilization and Axindegradation in Xenopus egg extract. Using an Axin mutant that does not degrade in response to LRP6, we demonstrate that LRP6 can

stabilize P-catenin in the absence of Axin turnover. Through experiments in egg extract and reconstitution with purified proteins, weidentify a mechanism whereby LRP6 stabilizes beta-catenin independently of Axin degradation by directly inhibiting GSK3'sphosphorylation of beta-catenin.

3.外文期刊 Oosterveen. T.Couldreuse. DYM.Yang. PT.Fraser. E.Bergsma. J.Dale. TC.Korswagen. HC Twofunctionally distinct Axin-like proteins regulate canonical Wnt signaling in C-elegans

Axin is a central component of the canonical Writ signaling pathway that interacts with the adenomatous polyposis coli proteinAPC and the kinase GSK3 beta to downregulate the effector l3-catenin. In the nematode Caenorhabditis elegans, canonical Wnt signalingis negatively regulated by the highly divergent Axin ortholog PRY-1. Mutation of pry-1 leads to constitutive activation of BAR-I/beta-catenin-dependent Writ signaling and results in a range of developmental defects. The pty-1 null phenotype is however notfully penetrant, indicating that additional factors may partially compensate for PRY-I function. Here, we report the cloning andfunctional analysis of a second Axin-like protein, which we named AXL-1. We show that despite considerable sequence divergence withPRY-1 and other Axin family members, AXL-1 is a functional Axin ortholog. AXL-1 functions redundantly with PRY-I in negativelyregulating BAR-1/beta-catenin signaling in the developing vulva and the Q neuroblast lineage. In addition, AXL-1 functions

independently of PRY-I in negatively regulating canonical Writ signaling during excretory cell development. In contrast to vertebrateAxin and the related protein Conductin, AXL-1 and PRY-1 are not functionally equivalent. We conclude that Axin function in C. elegansis divided over two different Axin orthologs that have specific functions in negatively regulating canonical Writ signaling. (c) 2007Elsevier Inc. All rights reserved.

4.外文期刊 Chia. IV.Costantini. F Mouse axin and Axin2/conductin proteins are functionallyequivalent in vivo

Axin is a central component of the canonical Wnt signal transduction machinery, serving as a scaffold for the beta-catenin

destruction complex. The related protein Axin2/Conductin, although less extensively studied, is thought to perform similar functions.Loss of Axin causes early embryonic lethality, while Axin2-null mice are viable but have craniofacial defects. Mutations in eithergene contribute to cancer in humans. The lack of redundancy between Axin and Axin2 could be due to their different modes of

expression: while Axin is expressed ubiquitously, Axin2 is expressed in tissue- and developmental-stage-specific patterns, and itstranscription is induced by canonical Wnt signaling. Alternatively, the two proteins might have partially different functions, ahypothesis supported by the observation that they differ in their subcellular localizations in colon epithelial cells. To test thefunctional equivalence of Axin and Axin2 in vivo, we generated knockin mice in which the Axin gene was replaced with Myc-tagged Axinor Axin2 cDNA. Mice homozygous for the resulting alleles, Axin(Ax) or Axin(Ax2), express no endogenous Axin but express either Myc-Axin or Myc-Axin2 under the control of the Axin locus. Both Axin(Ax/Ax) and Axin(Ax2/Ax2) homozygotes are apparently normal andfertile, demonstrating that the Axin and Axin2 proteins are functionally equivalent.

5.OA论文 Willert. Karl.Shibamoto. Sayumi.Nusse. Roel Wnt-induced dephosphorylation of Axin releasesβ-catenin from the Axin complex

The stabilization of β-catenin is a key regulatory step during cell fate changes and transformations to tumor cells. Severalinteracting proteins, including Axin, APC, and the protein kinase GSK-3β are implicated in regulating β-catenin phosphorylation andits subsequent degradation. Wnt signaling stabilizes β-catenin, but it was not clear whether and how Wnt signaling regulates the β-catenin complex. Here we show that Axin is dephosphorylated in response to Wnt signaling. The dephosphorylated Axin binds β-cateninless efficiently than the phosphorylated form. Thus, Wnt signaling lowers Axin’s affinity for β-catenin, thereby disengaging β-catenin from the degradation machinery.

6.外文期刊 Julius MA..Hsu W..Fitzpatrick E..Jho E..Fagotto F. Costantini F..Kitajewski J..SchelbertB. Domains of Axin and disheveled required for interaction and function in Wnt signaling

Disheveled blocks the degradation of beta-catenin in response to Wnt signal by interacting with the scaffolding protein, Axin. To

define this interaction in detail we undertook a mutational and binding analysis of the murine Axin and Disheveled proteins. The DIXdomain of Axin was found to be important for association with Disheveled and two other regions of Axin (between residues 1-168 and600-810) mere identified that can promote the association of Axin and Disheveled. We found that the DM domain of Disheveled iscritical for association with Axin in vivo and for Disheveled activity. The Disheveled DIX domain controlled the ability of

Disheveled to induce the accumulation of cytosolic beta-catenin whereas the PDZ domain was not essential to this function. (C) 2000Academic Press. [References: 30]

7.外文期刊 Primot A..Gompel M..Borgne A..Liabeuf S..Romette JL..Jho EH..Costantini F..Meijer L..Baratte B. Purification of GSK-3 by affinity chromatography on immobilized axin

Glycogen synthase kinase 3 (GSK-3), an element of the Wnt signalling pathway, plays a key role in numerous cellular processesincluding cell proliferation, embryonic development, and neuronal functions. It is directly involved in diseases such as cancer (bycontrolling apoptosis and the levels of beta -catenin and cyclin D1), Alzheimer's disease (tau hyperphosphorylation), and diabeteslas a downstream element of insulin action, GSK-3 regulates glycogen and lipid synthesis). We describe here a rapid and efficientmethod for the purification of GSK-3 by affinity chromatography on an immobilized fragment of axin. Axin is a docking protein whichinteracts with GSK-3 beta, beta -catenin, phosphatase 2A, and APC. A polyhistidine-tagged;ed axin peptide (residues 419 - 672) wasproduced in Escherichia coli and either immobilized on Ni-NTA agarose beads or purified and immobilized on CNBr-activated Sepharose4B. These \"Axin-His6\" matrices were found to selectively bind recombinant rat GSK-3 beta and native GSK-3 from yeast, sea urchinembryos, and porcine brain. The affinity-purified enzymes displayed high kinase activity. This single step purification methodprovides a convenient tool to follow the status of GSK-3 (protein level, phosphorylation state, kinase activity) under various

physiological settings. It also provides a simple and efficient way to purify large amounts of active recombinant or native GSK-3 forscreening purposes. (C) 2000 Academic Press. [References: 50]

8.外文期刊 Schwarz-Romond. T.Merrifield. C.Nichols. BJ.Bienz. M The Wnt signalling effectorDishevelled form dynamic protein assemblies rather than stabile associations with cytoplasmicvesicles

Dishevelled is a crucial effector upstream in the Wnt signalling pathway, but the molecular mechanism by which it transduces theWnt signal remains elusive. Dishevelled is a cytoplasmic protein with a strong tendency to form puncta, which correlates with itspotent activity in stimulating Wnt signal transduction when overexpressed. These puncta are thought to reflect cytoplasmic vesicles.However, we show here that the mammalian Dishevelled protein Dvl2 does not colocalise with known vesicle markers for clathrin-mediated or clathrin-independent endocytic pathways. Furthermore, Dvl2 puncta do not stain with lipid dyes, indicating that thesepuncta do not contain membranes. Instead, our evidence from live imaging by TIRF microscopy of Dvl2 tagged with green fluorescentprotein (GFP-Dvl2) revealed that these puncta move in and out of the evanescent field near the plasma membrane in an undirectedfashion, and that they can grow by collision and fusion. Furthermore, high-resolution confocal microscopy and photobleaching

experiments indicate that the GFP-Dvl2 puncta are protein assemblies; there is a constant exchange of GIFP-Dvl2 between puncta and adiffuse cytoplasmic pool, which, therefore, are in a dynamic equilibrium with each other. The same is true for the DIX domain of Dvl2itself and also for Axin-GFP, which equilibrates between the punctate and cytosolic pools. Our evidence indicates that Dvl2 and Axinpuncta are dynamic protein assemblies rather than cytoplasmic vesicles.

9.学位论文 徐洪涛 Axinβ-catenin的表达与肺癌的关系 2006

β-连环素(β-catenin)既是Wnt信号传导通路中的关键分子，又是E-cadherin/catenin复合体中的重要成员。当β-catenin在细胞核内蓄积时，能激活Wnt信号传导通路，启动靶基因转录，导致细胞增殖、侵袭和转移。Axin(Axisinhibitionprotein)是Wnt信号传导通路的重要负性调节因子，介导β-catenin磷酸化，促进其降解。人类肿瘤中，这些重要分子的相关作用如何尚不清楚，分析其表达、探索其机制对于防治人类肺癌意义重大。本研究探讨Axin和β-catenin在肺癌中的表达和β-catenin突变情况，分析它们与各临床病理因素的关系，揭示Axinβ-catenin和诱导肺癌细胞凋亡的机制。 方法：

(1)本研究采用44例新鲜肺癌及癌旁正常肺组织标本，均来自中国医科大学附属第一临床学院2003～2004年行外科切除手术的肺癌患者，患者术前均未接受过放化疗。

提取组织蛋白，采用考马斯亮蓝法进行蛋白定量。取等量蛋白，进行SDS-聚丙烯酰胺凝胶电泳和转印，一抗(anti-Axin1∶50稀释，Anti-β-actin1∶500稀释)和辣根过氧化物酶标记二抗(1∶50稀释)孵育后DAB显色。以β-actin为内对照，计算Axin的相对表达量。

使用Trizol试剂提取组织总RNA后，逆转录获得cDNA，均按说明书操作。PCR扩增Axin，产物长度为452bp，产物使用1.5％琼脂糖凝胶电泳检测观察。以β-actin为内对照，计算Axin的相对表达量。

(2)100例肺鳞癌、腺癌及对应的癌旁正常肺组织标本来自中国医科大学附属第一临床学院2001～2003年外科手术切除之原发性肺癌及癌周正常肺组织，患者术前均未接受过放化疗。

标本用中性溶液固定，石蜡包埋，制成4μm切片，经脱蜡，脱苯，水化后，采用链菌素抗生物素蛋白-过氧化物酶免疫组化法(S-P法)检测β-catenin蛋白和Axin蛋白表达，以PBS代替一抗作为阴性对照，以正常肺组织为阳性对照。结果判定：β-catenin正常阳性表达定位于细胞膜，每张切片随机选取10个高倍视野，每个视野计数100个瘤细胞，计数阳性细胞百分比。无着色为阴性(-)，膜阳性瘤细胞数＞90％为表达正常，≤90％为表达降低。10％以上瘤细胞核和(或)浆染色为核或浆表达。表达降低和胞浆、胞核表达统归为异常表达。Axin正常阳性表达定位于细胞浆，无着色和阳性瘤细胞数＜40％为阴性表达(-)，阳性瘤细胞数≥40％为阳性表达(+)。

采用酚-氯仿-异戊醇法提取肺癌标本DNA。PCR扩增β-catenin基因第三外显子，产物长度为199bp，经8％SDS聚丙烯酰胺凝胶电泳，银染后与DNA标准进行比较，鉴定扩增产物。PCR产物由上海联合基因公司纯化和测序。

(3)使用含10％小牛血清的RPMI10培养液，在37℃，含5％CO2的培养箱内培养肺癌PG细胞系。在35mm培养皿上接种2×105PG细胞，培养24h，待细胞数达到90％-95％后，转染Axin基因，按说明书操作，以未转染和转染空载体的PG细胞为对照。

免疫荧光：分别于转染后48h和72h取出转染组及对照组细胞爬片，丙酮固定10min。TritonX-100处理，血清封闭后，分别滴加FLAG、Axin、β-catenin和TCF-4一抗，4℃孵育过夜。避光加罗丹明(TRITC)和FITC标记二抗，DAPI复染细胞核后，荧光显微镜观察。

RT-PCR：收集转染组及对照组细胞，提取总RNA并反转录成cDNA，分别扩增Axin、β-catenin和TCF-4，以β-actin为内参。扩增产物经1.5％琼脂糖凝胶电泳后，成像分析。

流式细胞术：收集转染组及对照组细胞，95％乙醇固定，将细胞密度调至1×106/ml，PI染色后，流式细胞仪检测细胞周期和细胞凋亡情况，用ModfitLTV3.0软件分析结果。

(4)使用SPSS13.0统计软件进行数据处理，以P＜0.05为有统计学意义。 结果：

(1)44例新鲜肺癌组织中Axin蛋白的表达量明显低于正常肺组织(t=-2.819；P=0.007)。AxinmRNA的表达量也明显低于癌旁正常肺组织(t=-2.513；P=0.016)。Axin的蛋白表达与mRNA表达相关(相关系数：0.301；P=0.047)，但与肺癌的临床病理特征之间未发现明显相关性。(2)肺癌中β-catenin的异常表达率为80.0％，其中核表达阳性率为26.0％。高、中分化和低分化肺癌中，β-catenin的异常表达率分别为70.0％(35/50)和

90.0％(45/50)，差异有显著性(P=0.012)。有淋巴结转移和无淋巴结转移肺癌中β-catenin异常表达率分别为87.3％(48/55)和1.1％(32/45)，有明显差异(P=0.044)。Axin的阳性表达率为48.0％，高、中分化和低分化肺癌中，Axin的阳性率分别为60.0％(30/50)和36.0％(18/50)，差异有显著性

(P=0.016)。Ⅰ、Ⅱ、Ⅲ期肺癌中，Axin的阳性率分别为46.3％(19/41)、76.5％(13/17)和38.1％(16/42)，Ⅰ期和Ⅱ期(P=0.036)、Ⅱ期和Ⅲ期(P=0.008)均有显著性差异。在β-catenin核表达阳性的病例中，Axin阳性表达率为15.4％(4/26)，显著低于β-catenin核表达阴性的病例59.5％(44/74)(P＜0.001)。100例肺癌标本中未发现β-catenin基因第三外显子突变。

(3)将Axin基因导入肺癌PG细胞系后，Axin的mRNA和蛋白表达均明显增加，蛋白表达定位于细胞浆和细胞核，β-catenin蛋白的表达明显减少，但mRNA表达无明显变化，同时TCF-4的蛋白和mRNA表达均明显下降。流式细胞术检测发现，转染Axin基因后，PG细胞的凋亡率明显增加，但细胞周期变化不明显。 结论：

(1)肺癌组织中Axin的表达量明显低于正常肺组织。Axin的表达与肺鳞癌、腺癌的分期、低分化和β-catenin的细胞核蓄积负相关。Axin的表达增加能促进β-catenin蛋白的降解，抑制TCF-4的表达并诱导肺癌细胞的凋亡。Axin的表达缺失可能是肺癌恶性增殖的重要原因之一。

(2)β-catenin的异常表达与肺鳞癌、腺癌的低分化和淋巴结转移相关，其基因第三外显子突变不是肺癌中β-catenin异常蓄积的主要原因。

10.外文期刊 Wen Luo.Sheng-Cai Lin Axin: A Master Scaffold for Multiple Signaling Pathways

Axin was originally identified from the characterization of the Fused locus, the disruption of which leads to duplication of axisand embryonic lethality. It is a multidomain protein that interacts with multiple proteins and functions as a negative regulator ofWnt signaling by down-regulating the |3-catenin levels. Recently, it was demonstrated that Axin also plays an important role in a JNKsignaling pathway. Axin utilizes discriminatory domains for its distinct roles in the Wnt pathway and in the Axin/ JNK pathway. Herewe review the data that show how Axin regulates multiple signaling pathways by serving as a scaffold protein, controlling diversecellular functions in proliferation, fate determination, and suppression of tumorigenesis.

本文链接：http://d.g.wanfangdata.com.cn/Periodical_zgswhxyfzswxb200604005.aspx授权使用：哈尔滨医科大学(hebykdx)，授权号：6be2e145-bbcd-4b70-b688-9e10009d624f

下载时间：2010年10月15日