Regulating the stability of TGFβ receptors and Smads

Abstract

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

p21-activated Kinase 2 (PAK2) Inhibits TGF-β Signaling in Madin-Darby Canine Kidney (MDCK) Epithelial Cells by Interfering with the Receptor-Smad Interaction

“…Although the canonical Smad-mediated signaling is relatively simple, it is precisely controlled at different levels from the availability and activation of extracellular ligands, the activity and stability of membrane receptors to the activity, stability and localization of Smad proteins in the cytoplasm or in the nucleus (15,35,(37)(38)(39).…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…The signaling cascade is mediated by the phosphorylation of receptor regulated Smads (R-Smads), which are represented by Smad2 and Smad3 for the TGF-β family. Phosphorylated R-Smads form a complex with the co-Smad, Smad4 [215]. Once formed, the complex is translocated to the nucleus where it recruits transcriptional coactivators such as p300 and CBP to induce the acetylation and activation of the expression of TGF-β target genes.…”

Endocytic regulation of TGF-β signaling

“…The mechanisms regulating the stability of TGF-b receptors and Smad proteins are reviewed in detail by Lönn et al [107] .…”