Axin is a scaffold protein in TGF-β signaling that promotes degradation of Smad7 by Arkadia

被引:144
作者
Liu, Wei
Rui, Hongliang
Wang, Jifeng
Lin, Shuyong
He, Ying
Chen, Mingliang
Li, Qinxi
Ye, Zhiyun
Zhang, Suping
Chan, Siu Chiu
Chen, Ye-Guang
Han, Jiahuai
Lin, Sheng-Cai [1 ]
机构
[1] Hong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
[2] Xiamen Univ, Key Lab Cell Biol & Tumor Cell Engn, Sch Life Sci, Minist Educ, Fujian, Peoples R China
[3] Tsing Hua Univ, State Key Lab Biomembrane & Membrane Biotechnol, Dept Biol Sci & Biotechnol, Beijing 100084, Peoples R China
[4] Scripps Res Inst, Dept Immunol, La Jolla, CA USA
关键词
Arkadia; Axin; Smad7; TGF-beta; ubiquitination;
D O I
10.1038/sj.emboj.7601057
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
TGF-beta signaling involves a wide array of signaling molecules and multiple controlling events. Scaffold proteins create a functional proximity of signaling molecules and control the specificity of signal transduction. While many components involved in the TGF-beta pathway have been elucidated, little is known about how those components are coordinated by scaffold proteins. Here, we show that Axin activates TGF-beta signaling by forming a multimeric complex consisting of Smad7 and ubiquitin E3 ligase Arkadia. Axin depends on Arkadia to facilitate TGF-beta signaling, as their small interfering RNAs reciprocally abolished the stimulatory effect on TGF-beta signaling. Specific knockdown of Axin or Arkadia revealed that Axin and Arkadia cooperate with each other in promoting Smad7 ubiquitination. Pulse-chase experiments further illustrated that Axin significantly decreased the half-life of Smad7. Axin also induces nuclear export of Smad7. Interestingly, Axin associates with Arkadia and Smad7 independently of TGF-beta signal, in contrast to its transient association with inactive Smad3. However, coexpression of Wnt-1 reduced Smad7 ubiquitination by down-regulating Axin levels, underscoring the importance of Axin as an intrinsic regulator in TGF-beta signaling.
引用
收藏
页码:1646 / 1658
页数:13
相关论文
共 48 条
[1]   TGFβ and Wnt pathway cross-talk [J].
Attisano, L ;
Labbé, E .
CANCER AND METASTASIS REVIEWS, 2004, 23 (1-2) :53-61
[2]   Determinants of specificity in TGF-β signal transduction [J].
Chen, YG ;
Hata, A ;
Lo, RS ;
Wotton, D ;
Shi, YG ;
Pavletich, N ;
Massagué, J .
GENES & DEVELOPMENT, 1998, 12 (14) :2144-2152
[3]   Mouse axin and Axin2/conductin proteins are functionally equivalent in vivo [J].
Chia, IV ;
Costantini, F .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (11) :4371-4376
[4]   Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of β-catenin [J].
Cong, F ;
Varmus, H .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (09) :2882-2887
[5]   Ubiquitin-mediated degradation:: A mechanism for fine-tuning TGF-β signaling [J].
Datto, M ;
Wang, XF .
CELL, 2005, 121 (01) :2-4
[6]   Distinct endocytic pathways regulate TGF-β receptor signalling and turnover [J].
Di Guglielmo, GM ;
Le Roy, C ;
Goodfellow, AF ;
Wrana, JL .
NATURE CELL BIOLOGY, 2003, 5 (05) :410-421
[7]   Germ-layer specification and control of cell growth by ectodermin, a Smad4 ubiquitin ligase [J].
Dupont, S ;
Zacchigna, L ;
Cordenonsi, M ;
Soligo, S ;
Adorno, M ;
Rugge, M ;
Piccolo, S .
CELL, 2005, 121 (01) :87-99
[8]   Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation [J].
Ebisawa, T ;
Fukuchi, M ;
Murakami, G ;
Chiba, T ;
Tanaka, K ;
Imamura, T ;
Miyazono, K .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (16) :12477-12480
[9]   Interaction between smad7 and β-catenin:: Importance for transforming growth factor β-induced apoptosis [J].
Edlund, S ;
Lee, SY ;
Grimsby, S ;
Zhang, SH ;
Aspenström, P ;
Heldin, CH ;
Landström, M .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (04) :1475-1488
[10]   Induction of the mammalian node requires Arkadia function in the extraembryonic lineages [J].
Episkopou, V ;
Arkell, R ;
Timmons, PM ;
Walsh, JJ ;
Andrew, RL ;
Swan, D .
NATURE, 2001, 410 (6830) :825-830