Sumoylation of Smad3 stimulates its nuclear export during PIASy-mediated suppression of TGF-β signaling

Imoto, Seiyu; Ohbayashi, Norihiko; Ikeda, Osamu; Kamitani, Shinya; Muromoto, Ryuta; Sekine, Yoshifumi; Matsuda, Tadashi

doi:10.1016/j.bbrc.2008.03.116

Cited by 48 publications

(34 citation statements)

References 26 publications

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“…Sumoylation of SMAD3 by the protein inhibitor of activated Stat y (PIASy; PIAS4) sumoligase promotes its nuclear export in mammalian cells (Imoto et al, 2008). Sumoylation of Medea, by an as yet unidentified sumoligase, also promotes its nuclear export, providing negative regulation that restricts the competence of early Drosophila embryonic cells to respond to Dpp (Miles et al, 2008).…”

Section: Regulation Of Smad Nuclear Shuttlingmentioning

confidence: 99%

The regulation of TGFβ signal transduction

2009

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Transforming growth factor  (TGF) pathways are implicated in metazoan development, adult homeostasis and disease. TGF ligands signal via receptor serine/threonine kinases that phosphorylate, and activate, intracellular Smad effectors as well as other signaling proteins. Oligomeric Smad complexes associate with chromatin and regulate transcription, defining the biological response of a cell to TGF family members. Signaling is modulated by negative-feedback regulation via inhibitory Smads. We review here the mechanisms of TGF signal transduction in metazoans and emphasize events crucial for embryonic development. IntroductionThe human transforming growth factor  (TGF) family consists of 33 members, most of which encode dimeric, secreted polypeptides that control developmental processes, ranging from gastrulation and body axis asymmetry to organ-specific morphogenesis and adult tissue homeostasis (reviewed by Derynck and Miyazono, 2008). In addition to TGFs, this family includes the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins and nodal. The TGF family is conserved throughout metazoan evolution. At the cellular level, TGF family members regulate cell growth, differentiation, adhesion, migration and death, in a developmental context-dependent and cell type-specific manner. For example, TGF more often inhibits, but sometimes also stimulates, cell proliferation (reviewed by Yang and Moses, 2008). Furthermore, nodal signaling sometimes inhibits, whereas BMP promotes, cell differentiation, as in stem cells (Watabe and Miyazono, 2009). As TGF ligands act multifunctionally in numerous tissue types, they also play complex roles in various human diseases, ranging from autoimmune to cardiovascular diseases and cancer (reviewed by Gordon and Blobe, 2008;Massagué, 2008).Here we review the core components of the TGF family and their signaling engines, as part of a Minifocus in this issue on TGF signaling (see Box 1), and discuss emerging concepts concerning the regulatory mechanisms of TGF pathways at the receptor, cytoplasmic and nuclear level. We also highlight recent discoveries that are of particular developmental relevance. The TGF familyThe development of the axes and the asymmetry of the animal body depends on the localized action of extracellular signals, such as the Wnt, nodal and BMP ligands. Gradients of these ligands, their extracellular regulators and the competence of receptors in responding cells, play important roles during tissue morphogenesis (Affolter and Basler, 2007;Smith and Gurdon, 2004). TGF family members also contribute to tissue patterning and are important regulators of stem cell self-renewal and differentiation (see Box 2) (De Robertis and Kuroda, 2004;Watabe and Miyazono, 2009).The TGF morphogens include numerous secreted and conserved polypeptides (Table 1), which emerged at the onset of multicellular (metazoan) life (Huminiecki et al., 2009). Structurally, this family is characterized by a specific three-dimensional fold and by a conser...

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Section: Regulation Of Smad Nuclear Shuttlingmentioning

confidence: 99%

The regulation of TGFβ signal transduction

2009

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“…In addition to being ubiquitinated, Smad3 has also been shown to be sumoylated by the sumoylationspecific E3 ligase, protein inhibitor of activated STAT (PIASy) [55][56][57]. However, this Ub-like modification was reported to repress Smad transcriptional activity by inhibiting DNA-binding and stimulating nuclear export of Smad3 rather than affecting its degradation.…”

Section: Regulation Of R-smad Stabilitymentioning

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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“…PIAS4 suppresses the TGFβ pathway, in part, by SUMOylating SMAD3 and causing its nuclear export (Imoto et al, 2003(Imoto et al, , 2008Long et al, 2003). Here we show that FIEL1 appears to promote TGFβ signaling and fibrosis by destabilizing PIAS4.…”

Section: Discussionmentioning

confidence: 57%

“…PIAS4 is known to possess small ubiquitin-like modifier (SUMO) E3 ligase activity within its RING-type domain (Imoto et al, 2004). It promotes the sumoylation of SMAD3, in turn stimulating its nuclear export and inhibiting SMAD3/4-driven pro-fibrotic transcription (Lee et al, 2003;Imoto et al, 2008). Furthermore, PIAS4 directly recruits and interacts with histone deacetylase 1…”

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confidence: 99%