Jab1 antagonizes TGF-β signaling by inducing Smad4 degradation

Authors

  • Mei Wan,

    1. Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL, USA
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  • Xuesong Cao,

    1. Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL, USA
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  • Yalei Wu,

    1. Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL, USA
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  • Shuting Bai,

    1. Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL, USA
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  • Liyu Wu,

    1. Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL, USA
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  • Xingming Shi,

    1. Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL, USA
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  • Ning Wang,

    1. Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL, USA
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  • Xu Cao

    Corresponding author
    1. Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL, USA
    • Corresponding author. Tel: +1 205 934 0162; Fax: +1 205 934 1775; E-mail: cao@path.uab.edu

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Abstract

Tumor suppressor Smad4 is the common signaling effector in the transforming growth factor β (TGF-β) superfamily. Phosphorylated regulatory Smads (R-Smads) interact with Smad4, and the complex translocates into the nucleus to regulate gene transcription. Proper TGF-β signaling requires precise control of Smad functions. Smurfs have been shown to mediate the degradation of R-Smads but not the common-partner Smad4. We report a novel mechanism of Smad4 degradation. Jab1 interacts directly with Smad4 and induces its ubiquitylation for degradation. Jab1 was initially identified as a co-activator of c-Jun, and it also induces degradation of cell cycle inhibitor p27 and tumor suppressor p53. Ectopic expression of Jab1 decreased endogenous Smad4 steady-state levels. The 26S proteasome inhibitors lactacystin and MG132 reduced the degradation rate of Smad4 protein. Examination of the effects of JAB1-induced Smad4 degradation indicates that Jab1 inhibited TGF-β-induced gene transcription. Our data suggest that Jab1 antagonizes TGF-β function by inducing degradation of Smad4 through a distinct degradation pathway.

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