Jab1/CSN5, a Component of the COP9 Signalosome, Regulates Transforming Growth Factor β Signaling by Binding to Smad7 and Promoting Its Degradation

Kim, Byung-Chul; Lee, Hojae; Park, Seok Hee; Lee, Sae Ra; Karpova, Tatiana S.; McNally, James G.; Felici, Angelina; Lee, Dug Keun; Kim, Seong‐Jin

doi:10.1128/mcb.24.6.2251-2262.2004

Cited by 107 publications

(59 citation statements)

References 63 publications

(72 reference statements)

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“…After binding to TβR-I, Smurfs 1 and 2 induce ubiquitin-mediated degradation of TβR-I. In addition, Jab1/CSN5, which is a component of the COP9 (constitutively photomorphogenic 9) signalosome complex, has been reported to associate with Smad7, and induce nuclear export and degradation of Smad7 [20]. In contrast, some ubiquitin ligases have been reported to degrade negative regulators of the TGF-β/ BMP pathway, and enhance signalling by members of the TGF-β superfamily.…”

Section: Introductionmentioning

confidence: 99%

NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor

Kuratomi

Komuro

Goto

et al. 2005

Biochemical Journal

197

143

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Inhibitory Smad, Smad7, is a potent inhibitor of TGF-β (transforming growth factor-β) superfamily signalling. By binding to activated type I receptors, it prevents the activation of R-Smads (receptor-regulated Smads). To identify new components of the Smad pathway, we performed yeast two-hybrid screening using Smad7 as bait, and identified NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) as a direct binding partner of Smad7. NEDD4-2 is structurally similar to Smurfs (Smad ubiquitin regulatory factors) 1 and 2, which were identified previously as E3 ubiquitin ligases for R-Smads and TGF-β superfamily receptors. NEDD4-2 functions like Smurfs 1 and 2 in that it associates with TGF-β type I receptor via Smad7, and induces its ubiquitin-dependent degradation. Moreover, NEDD4-2 bound to TGF-β-specific R-Smads, Smads 2 and 3, in a ligand-dependent manner, and induced degradation of Smad2, but not Smad3. However, in contrast with Smurf2, NEDD4-2 failed to induce ubiquitination of SnoN (Ski-related novel protein N), although NEDD4-2 bound to SnoN via Smad2 more strongly than Smurf2. We showed further that overexpressed NEDD4-2 prevents transcriptional activity induced by TGF-β and BMP, whereas silencing of the NEDD4-2 gene by siRNA (small interfering RNA) resulted in enhancement of the responsiveness to TGF-β superfamily cytokines. These data suggest that NEDD4-2 is a member of the Smurf-like C2-WW-HECT (WW is Trp-Trp and HECT is homologous to the E6-accessory protein) type E3 ubiquitin ligases, which negatively regulate TGF-β superfamily signalling through similar, but not identical, mechanisms to those used by Smurfs.

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Section: Introductionmentioning

confidence: 99%

NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor

Kuratomi

Komuro

Goto

et al. 2005

Biochemical Journal

197

143

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“…A few interesting associations that could become altered via altered CSN function are the cyclin-dependent kinase inhibitors p27 (35,43), p57 (18), and p21 (14) and their transcriptional regulators (i.e., SMAD4 and SMAD7; refs. [44][45][46][47] as well as several cyclins (cyclin D1, cyclin E, and cyclin B1; refs. 17,20,24,28).…”

Section: Cell Cyclementioning

confidence: 99%

The Emerging Role of the COP9 Signalosome in Cancer

Richardson

Zundel

2005

Molecular Cancer Research

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In the last several years, multiple lines of evidence have suggested that the COP9 signalosome (CSN) plays a significant role in the regulation of multiple cancers and could be an attractive target for therapeutic intervention. First, the CSN plays a key role in the regulation of Cullin-containing ubiquitin E3 ligases that are central mediators of a variety of cellular functions essential during cancer progression. Second, several studies suggest that the individual subunits of the CSN, particularly CSN5, might regulate oncogenic and tumor suppressive functions independently of, or coordinately with, the CSN holocomplex. Thus, deregulation of CSN subunit function can have a dramatic effect on diverse cellular functions, including the maintenance of DNA fidelity, cell cycle control, DNA repair, angiogenesis, and microenvironmental homeostasis that are critical for tumor development. Additionally, clinical studies have suggested that the expression or localization of some CSN subunits correlate to disease progression or clinical outcome in a variety of tumor types. Although the study of CSN function in relation to tumor progression is in its infancy, this review will address current studies in relation to cancer initiation, progression, and potential for therapeutic intervention. (Mol Cancer Res 2005;3(12):645 -53)

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“…Jab1/CSN5, a component of the COP9 signalosome complex, also associates with Smad7 to cause its translocation from the nucleus to the cytoplasm and promote its ubiquitination and degradation [106]. As Jab1/CSN5 is not an E3 ubiquitin ligase itself, it must serve as an adaptor in promoting Smad7 ubiquitin-mediated degradation.…”

Section: I-smads and T β Rsmentioning

confidence: 99%

To (TGF)β or not to (TGF)β: Fine-tuning of Smad signaling via post-translational modifications

Wrighton

Feng

2008

Cellular Signalling

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Jab1/CSN5, a Component of the COP9 Signalosome, Regulates Transforming Growth Factor β Signaling by Binding to Smad7 and Promoting Its Degradation

Cited by 107 publications

References 63 publications

NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor

NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor

The Emerging Role of the COP9 Signalosome in Cancer

To (TGF)β or not to (TGF)β: Fine-tuning of Smad signaling via post-translational modifications

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