Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change

被引：225

作者：

Gallagher, E

Gao, M

Liu, YC

Karin, M

机构：

[1] Univ Calif San Diego, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA

[2] Pharmacopeia Drug Discovery, Cranbury, NJ 08512 USA

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

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2006年 / 103卷 / 06期

关键词：

D O I：

10.1073/pnas.0510664103

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The E3 ubiquitin (Ub) ligase Itch is a critical regulator of T helper 2 (Th2) cytokine production through its ability to induce Ub-dependent JunB degradation. After T cell receptor engagement, Itch undergoes JINK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222, which are located within a Pro-rich region. Phosphorylation of these sites is necessary and sufficient for disrupting an inhibitory interaction between the WW domain of Itch and its catalytic HECT (Homologous to E6-AP C Terminus) domain and induces a conformational change that greatly enhances the catalytic activity of Itch, a HECT E3 ligase found to be directly activated upon its phosphorylation.

引用

页码：1717 / 1722

页数：6

共 31 条

[1]

Boyle W J, 1991, Methods Enzymol, V201, P110

[2] NUCLEOTIDE-INDUCED CONFORMATIONAL-CHANGES IN THE ATPASE AND SUBSTRATE-BINDING DOMAINS OF THE DNAK CHAPERONE PROVIDE EVIDENCE FOR INTERDOMAIN COMMUNICATION [J].

BUCHBERGER, A ;

THEYSSEN, H ;

SCHRODER, H ;

MCCARTY, JS ;

VIRGALLITA, G ;

MILKEREIT, P ;

REINSTEIN, J ;

BUKAU, B .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (28) :16903-16910

[3] THE CHAPERONE FUNCTION OF DNAK REQUIRES THE COUPLING OF ATPASE ACTIVITY WITH SUBSTRATE-BINDING THROUGH RESIDUE E171 [J].

BUCHBERGER, A ;

VALENCIA, A ;

MCMACKEN, R ;

SANDER, C ;

BUKAU, B .

EMBO JOURNAL, 1994, 13 (07) :1687-1695

[4] ARF-BP1/mule is a critical mediator of the ARF tumor suppressor [J].

Chen, DL ;

Kon, N ;

Li, MY ;

Zhang, WZ ;

Qin, J ;

Gu, W .

CELL, 2005, 121 (07) :1071-1083

[5] Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel cell surface expression [J].

Debonneville, C ;

Flores, SY ;

Kamynina, E ;

Plant, PJ ;

Tauxe, C ;

Thomas, MA ;

Münster, C ;

Chraïbi, A ;

Pratt, JH ;

Horisberger, JD ;

Pearce, D ;

Loffing, J ;

Staub, O .

EMBO JOURNAL, 2001, 20 (24) :7052-7059

[6] A cytoplasmic inhibitor of the JNK signal transduction pathway [J].

Dickens, M ;

Rogers, JS ;

Cavanagh, J ;

Raitano, A ;

Xia, ZG ;

Halpern, JR ;

Greenberg, ME ;

Sawyers, CL ;

Davis, RJ .

SCIENCE, 1997, 277 (5326) :693-696

[7]

DiDonato J, 1996, MOL CELL BIOL, V16, P1295

[8] JNK is required for effector T-cell function but not for T-cell activation [J].

Dong, C ;

Yang, DD ;

Tournier, C ;

Whitmarsh, AJ ;

Xu, J ;

Davis, RJ ;

Flavell, RA .

NATURE, 2000, 405 (6782) :91-94

[9] Dysregulation of T lymphocyte function in itchy mice:: a role for itch in TH2 differentiation [J].

Fang, DY ;

Elly, C ;

Gao, BX ;

Fang, N ;

Altman, Y ;

Joazeiro, C ;

Hunter, T ;

Copeland, N ;

Jenkins, N ;

Liu, YC .

NATURE IMMUNOLOGY, 2002, 3 (03) :281-287

[10] Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase itch [J].

Gao, M ;

Labuda, T ;

Xia, Y ;

Gallagher, E ;

Fang, D ;

Liu, YC ;

Karin, M .

SCIENCE, 2004, 306 (5694) :271-275

← 1 2 3 4 →