Arkadia amplifies TGF-  superfamily signalling through degradation of Smad7

Koinuma, Daizo; Shinozaki, Masahiko; Komuro, Akiyoshi; Goto, Kouichiro; Saitoh, Masao; Hanyu, Aki; Ebina, Masahito; Nukiwa, Toshihiro; Miyazawa, Keiji; Imamura, Takeshi; Miyazono, Kohei

doi:10.1093/emboj/cdg632

Cited by 206 publications

(195 citation statements)

References 41 publications

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“…The best-studied I-Smad in this respect is Smad7, which acts not only as a mediator of ubiquitination and degradation of both the TGFb receptors and the Co-Smad (Figures 1 and 2) [23,24,61], but also as a carrier of phosphatases or a simple disruptor of protein interactions between R-Smads and Co-Smad or between R-Smads and type I receptors [9]. Furthermore, Smad7 is well established as a target of both Ub ligases and acetyl-transferases like p300/ CBP, but the impact of such regulation of Smad7 on the receptor/R-Smad/Co-Smad pathway remains poorly understood [23,24,73,74].…”

Section: Regulation Of Stability Of I-smads and Other Signaling Targetsmentioning

confidence: 99%

Regulating the stability of TGFβ receptors and Smads

et al. 2008

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Abbreviations: AIP4 (atrophin 1-interacting protein 4); BMP (bone morphogenetic protein); CHIP (carboxyl terminus of Hsc70-interacting protein); GSK3b (glycogen synthase kinase 3-b); HECT (homologous to E6-AP carboxyl terminus); MAPK (mitogen-activated protein kinase); NEDD4-2 (neural precursor cell expressed, developmentally downregulated 4-2); PIAS (protein inhibitor of activated Stat); Smurf (Smad ubiquitylation regulatory factor); STRAP (serine-threonine kinase receptorassociated protein); SUMO (small ubiquitin-like modifier); TbRI/TbRII (TGFb receptor type I and II); TGFb (transforming growth factor b); WWP1 (WW domain-containing protein 1); Ub (ubiquitin) npg Transforming growth factor β (TGFβ) controls cellular behavior in embryonic and adult tissues. TGFβ binding to serine/threonine kinase receptors on the plasma membrane activates Smad molecules and additional signaling proteins that together regulate gene expression. In this review, mechanisms and models that aim at explaining the coordination between several components of the signaling network downstream of TGFβ are presented. We discuss how the activity and duration of TGFβ receptor/Smad signaling can be regulated by post-translational modifications that affect the stability of key proteins in the pathway. We highlight links between these mechanisms and human diseases, such as tissue fibrosis and cancer. Regulating the stability of TGFβ receptors and Smads

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Section: Regulation Of Stability Of I-smads and Other Signaling Targetsmentioning

confidence: 99%

Regulating the stability of TGFβ receptors and Smads

et al. 2008

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“…The cDNA for Smurf2 was kindly provided by Dr X.-H. Feng (Departments of Surgery and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, U.S.A.) [14]. COS7 cells, HEK-293 cells, HEK-293T cells and HepG2 cells were transiently transfected using FuGENE6 (Roche Applied Science) or LIPOFECTAMINE 2000 reagent (Invitrogen) as described previously [22].…”

Section: Dna Construction and Transfectionmentioning

confidence: 99%

“…siRNAs (small interfering RNAs) were introduced into cells as described previously [22]. The following 21-mer oligonucleotide pairs were used for RNA interference: NEDD4-2 siRNA from nucleotides 727-747 (GenBank ® accession number AB007899), and NEDD4(CA).…”

Section: Rna Interference and Oligonucleotidesmentioning

confidence: 99%

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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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“…In addition to Smurfs and Smurf-like molecules the nuclear RING-domain ubiquitin ligase Arkadia has been shown to degrade Smad6/7 in cooperation with the scaffold protein Axin [104,105]. 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].…”

Section: I-smads and T β Rsmentioning

confidence: 99%