Itch E3 ligase-mediated regulation of TGF-β signaling by modulating Smad2 phosphorylation

被引：104

作者：

Bai, YL ^{[1
]}

Yang, C ^{[1
]}

Hu, K ^{[1
]}

Elly, C ^{[1
]}

Liu, YC ^{[1
]}

机构：

[1] La Jolla Inst Allergy & Immunol, Div Cell Biol, San Diego, CA 92121 USA

来源：

MOLECULAR CELL | 2004年 / 15卷 / 05期

关键词：

D O I：

10.1016/j.molcel.2004.07.021

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：

Protein ubiquitination has been implicated in the intracellular biochemical events transduced by TGF-beta receptor via different mechanisms including the degradation of Smads or their binding proteins. Here we show that loss of Itch E3 ligase in mouse embryonic fibroblasts (MEFs) results in reduced susceptibility of TGF-beta-induced cell growth arrest and decreased phosphorylation of Smad2, without apparent alteration in protein levels for Smad2, Smad4, and Smad7 in Itch(-/-) MEFs. Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch. Moreover, Itch facilitates complex formation between TGF-beta receptor and Smad2 and enhances TGF-beta-induced transcription. This study reveals a previously unrecognized positive TGF-beta signaling pathway via proteolysis-independent ubiquitination.

引用

页码：825 / 831

页数：7

共 28 条

[1] Signal transduction by the TGF-β superfamily
Attisano, L
Wrana, JL
[J]. SCIENCE, 2002, 296 (5573) : 1646 - 1647
[2] TGF-β induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation
Bonni, S
Wang, HR
Causing, CG
Kavsak, P
Stroschein, SL
Luo, KX
Wrana, JL
[J]. NATURE CELL BIOLOGY, 2001, 3 (06) : 587 - 595
[3] Datto MB, 1999, MOL CELL BIOL, V19, P2495
[4] Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain
Deng, L
Wang, C
Spencer, E
Yang, LY
Braun, A
You, JX
Slaughter, C
Pickart, C
Chen, ZJ
[J]. CELL, 2000, 103 (02) : 351 - 361
[5] Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation
Ebisawa, T
Fukuchi, M
Murakami, G
Chiba, T
Tanaka, K
Imamura, T
Miyazono, K
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (16) : 12477 - 12480
[6] Dysregulation of T lymphocyte function in itchy mice:: a role for itch in TH2 differentiation
Fang, DY
Elly, C
Gao, BX
Fang, N
Altman, Y
Joazeiro, C
Hunter, T
Copeland, N
Jenkins, N
Liu, YC
[J]. NATURE IMMUNOLOGY, 2002, 3 (03) : 281 - 287
[7] Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells
Fang, DY
Liu, YC
[J]. NATURE IMMUNOLOGY, 2001, 2 (09) : 870 - 875
[8] The ubiquitin system
Hershko, A
Ciechanover, A
[J]. ANNUAL REVIEW OF BIOCHEMISTRY, 1998, 67 : 425 - 479
[9] Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation
Kavsak, P
Rasmussen, RK
Causing, CG
Bonni, S
Zhu, HT
Thomsen, GH
Wrana, JL
[J]. MOLECULAR CELL, 2000, 6 (06) : 1365 - 1375
[10] Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-β signaling
Lin, X
Liang, M
Feng, XH
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (47) : 36818 - 36822

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