USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor

Long Zhang; FangFang Zhou; Yvette Drabsch; Rui Gao; B. Ewa Snaar-Jagalska; Craig Mickanin; Huizhe Huang; Kelly-Ann Sheppard; Jeff A. Porter; Chris X. Lu; Peter ten Dijke

doi:10.1038/ncb2522

USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor

Long Zhang, FangFang Zhou^*, Yvette Drabsch, Rui Gao, B. Ewa Snaar-Jagalska, Craig Mickanin, Huizhe Huang, Kelly-Ann Sheppard, Jeff A. Porter, Chris X. Lu, Peter ten Dijke

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

The stability and membrane localization of the transforming growth factor-beta (TGF-beta) type I receptor (T beta RI) determines the levels of TGF-beta signalling. T beta RI is targeted for ubiquitylation-mediated degradation by the SMAD7-SMURF2 complex. Here we performed a genome-wide gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of TGF-beta signalling. USP4 was found to directly interact with T beta RI and act as a deubiquitylating enzyme, thereby controlling T beta RI levels at the plasma membrane. Depletion of USP4 mitigates TGF-beta-induced epithelial to mesenchymal transition and metastasis. Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4. AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability. Moreover, AKT-induced breast cancer cell migration was inhibited by USP4 depletion and T beta RI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-beta and AKT signalling pathways.

Original language	English
Pages (from-to)	717-726
Number of pages	10
Journal	Nature Cell Biology
Volume	14
Issue number	7
DOIs	https://doi.org/10.1038/ncb2522
Publication status	Published - Jul 2012

Keywords

E3 UBIQUITIN LIGASE
MESENCHYMAL TRANSITION
DEPENDENT DEGRADATION
SIGNAL-TRANSDUCTION
CANCER PROGRESSION
CELL-MIGRATION
TARGETS
GROWTH
ACTIVATION
METASTASIS

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10.1038/ncb2522

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@article{07aac55b26534c51ad98f3a9396de979,

title = "USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor",

abstract = "The stability and membrane localization of the transforming growth factor-beta (TGF-beta) type I receptor (T beta RI) determines the levels of TGF-beta signalling. T beta RI is targeted for ubiquitylation-mediated degradation by the SMAD7-SMURF2 complex. Here we performed a genome-wide gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of TGF-beta signalling. USP4 was found to directly interact with T beta RI and act as a deubiquitylating enzyme, thereby controlling T beta RI levels at the plasma membrane. Depletion of USP4 mitigates TGF-beta-induced epithelial to mesenchymal transition and metastasis. Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4. AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability. Moreover, AKT-induced breast cancer cell migration was inhibited by USP4 depletion and T beta RI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-beta and AKT signalling pathways.",

keywords = "E3 UBIQUITIN LIGASE, MESENCHYMAL TRANSITION, DEPENDENT DEGRADATION, SIGNAL-TRANSDUCTION, CANCER PROGRESSION, CELL-MIGRATION, TARGETS, GROWTH, ACTIVATION, METASTASIS",

author = "Long Zhang and FangFang Zhou and Yvette Drabsch and Rui Gao and Snaar-Jagalska, {B. Ewa} and Craig Mickanin and Huizhe Huang and Kelly-Ann Sheppard and Porter, {Jeff A.} and Lu, {Chris X.} and {ten Dijke}, Peter",

year = "2012",

month = jul,

doi = "10.1038/ncb2522",

language = "English",

volume = "14",

pages = "717--726",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "7",

}

USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor. / Zhang, Long; Zhou, FangFang; Drabsch, Yvette; Gao, Rui; Snaar-Jagalska, B. Ewa; Mickanin, Craig; Huang, Huizhe; Sheppard, Kelly-Ann; Porter, Jeff A.; Lu, Chris X.; ten Dijke, Peter.

In: Nature Cell Biology, Vol. 14, No. 7, 07.2012, p. 717-726.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor

AU - Zhang, Long

AU - Zhou, FangFang

AU - Drabsch, Yvette

AU - Gao, Rui

AU - Snaar-Jagalska, B. Ewa

AU - Mickanin, Craig

AU - Huang, Huizhe

AU - Sheppard, Kelly-Ann

AU - Porter, Jeff A.

AU - Lu, Chris X.

AU - ten Dijke, Peter

PY - 2012/7

Y1 - 2012/7

N2 - The stability and membrane localization of the transforming growth factor-beta (TGF-beta) type I receptor (T beta RI) determines the levels of TGF-beta signalling. T beta RI is targeted for ubiquitylation-mediated degradation by the SMAD7-SMURF2 complex. Here we performed a genome-wide gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of TGF-beta signalling. USP4 was found to directly interact with T beta RI and act as a deubiquitylating enzyme, thereby controlling T beta RI levels at the plasma membrane. Depletion of USP4 mitigates TGF-beta-induced epithelial to mesenchymal transition and metastasis. Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4. AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability. Moreover, AKT-induced breast cancer cell migration was inhibited by USP4 depletion and T beta RI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-beta and AKT signalling pathways.

AB - The stability and membrane localization of the transforming growth factor-beta (TGF-beta) type I receptor (T beta RI) determines the levels of TGF-beta signalling. T beta RI is targeted for ubiquitylation-mediated degradation by the SMAD7-SMURF2 complex. Here we performed a genome-wide gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of TGF-beta signalling. USP4 was found to directly interact with T beta RI and act as a deubiquitylating enzyme, thereby controlling T beta RI levels at the plasma membrane. Depletion of USP4 mitigates TGF-beta-induced epithelial to mesenchymal transition and metastasis. Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4. AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability. Moreover, AKT-induced breast cancer cell migration was inhibited by USP4 depletion and T beta RI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-beta and AKT signalling pathways.

KW - E3 UBIQUITIN LIGASE

KW - MESENCHYMAL TRANSITION

KW - DEPENDENT DEGRADATION

KW - SIGNAL-TRANSDUCTION

KW - CANCER PROGRESSION

KW - CELL-MIGRATION

KW - TARGETS

KW - GROWTH

KW - ACTIVATION

KW - METASTASIS

U2 - 10.1038/ncb2522

DO - 10.1038/ncb2522

M3 - Article

VL - 14

SP - 717

EP - 726

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 7

ER -

USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor

Abstract

Keywords

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