Regulation of TGF-β Family Signaling by Inhibitory Smads

Abstract

Inhibitory Smads (I-Smads) have conserved carboxy-terminal MH2 domains but highly divergent amino-terminal regions when compared with receptor-regulated Smads (R-Smads) and common-partner Smads (co-Smads). Smad6 preferentially inhibits Smad signaling initiated by the bone morphogenetic protein (BMP) type I receptors ALK-3 and ALK-6, whereas Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. I-Smads also regulate some non-Smad signaling pathways. Here, we discuss the vertebrate I-Smads, their roles as inhibitors of Smad activation and regulators of receptor stability, as scaffolds for non-Smad signaling, and their possible roles in the nucleus. We also discuss the posttranslational modification of I-Smads, including phosphorylation, ubiquitylation, acetylation, and methylation.

Figure 1.

Structures of Smad proteins. Schematic representation of the structures of Smad6 and Smad7 (I-Smads), Smad3 (R-Smad), and Smad4 (co-Smad). The Leu-rich motif (LRM) is partially conserved in the Smad6 N domain, but its ability to recruit UbcH7 has yet to be determined. The Ser-Ser-X-Ser (SSXS) motif is only present in R-Smads. I-Smads, Inhibitory Smads; R-Smad, receptor-regulated Smad; co-Smad, common-partner Smad; PY, Pro-Tyr; PLDLS, Pro-Leu-Asp-Leu-Ser; Me, methylation site; Ac/Ub, acetylation and ubiquitylation site.

Figure 2.

Regulation of transforming growth factor β (TGF-β) family signaling through I-Smad association with activated type I receptors. (A) Inhibitory Smads (I-Smads) inhibit TGF-β family signaling via interactions with type I receptors and compete with receptor-regulated Smads (R-Smads) for receptor activation. The N domain of Smad7 associates with the MH2 domain and facilitates the interaction with type I receptors. (B) Smad ubiquitin regulatory factors (Smurfs) and other E3 ubiquitin ligases induce the degradation of receptors through interactions with I-Smads. UbcH7 is recruited to the Smad7–Smurf2 complex. Salt-inducible kinase (SIK) cooperates with the complex, whereas ubiquitin-specific peptidase 15 (USP15) counteracts the Smad7–Smurf2 complex. (C) The growth arrest and DNA damage protein 34 (GADD34)–PP1c complex induces dephosphorylation of activated type I receptors through interactions with I-Smads. (D) Toll-interacting protein (Tollip) interacts with Smad7 and ubiquitylated type I receptor to facilitate the endosomal localization of receptors, possibly leading to their lysosomal degradation.

Figure 3.

Molecules regulating the function of inhibitory Smads (I-Smads). In addition to homologous to the E6-accessory protein (HECT)-type E3 ligases (Smurf1, Smurf2, WWP1/Tiul1, and NEDD4-2), other proteins promote the association of I-Smads with activated type I receptors, although they do not directly induce type I receptor degradation. In contrast, PRMT1, UBE2O, AMSH, and TSC-22 inhibit the interaction of I-Smads with receptors and receptor-regulated Smads (R-Smads). Arkadia, RNF12, Jab1/CSN5, and Cbl-b induce the degradation of Smad7. Transcription of Smad7 is regulated by various transcription factors and repressors. microRNAs (miRNAs) inhibit translation or induce the decay of Smad7 messenger RNA (mRNA). Molecules that inhibit transforming growth factor β (TGF-β) family signaling by supporting the function of I-Smads are shown in red, and those that enhance TGF-β signaling by inhibiting I-Smad function are shown in blue.