The Smad pathway

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Abstract

Transforming growth factor-β superfamily member signals are conveyed through cell-surface serine/threonine kinase receptors to the intracellular mediators known as Smads. Activation of Smads causes their translocation from the cytoplasm to the nucleus where they function to control gene expression. In this review we will focus on proteins that modulate Smad activity, including SARA, for Smad Anchor for Receptor Activation, which functions during the initiation of signalling and on components of the ubiquitin-proteasome pathway, such as Smurf1, which can negatively regulate Smad signalling. In addition, we will summarize recent findings on the role of Smads as transcriptional co-modulators.

Section snippets

Mechanism of signalling by members of the TGFβ superfamily

Transforming growth factor-β (TGFβ) superfamily members are a group of related multifunctional polypeptide factors that control numerous cellular processes from the earliest stages of development to a variety of normal and abnormal cellular functions [1], [2]. The members of this superfamily elicit their biological effects through a family of transmembrane serine/threonine kinase receptors classified as type I or type II receptors [3], [4], [5], [6]. The current model for initiation of

The structure of Smads

While Smads do not appear to harbor any previously characterized protein modules, comparisons amongst Smads has revealed the presence of conserved amino (MH1) and carboxy-terminal (MH2) domains and a central, poorly conserved, linker region [4], [5], [7], [8], [9], [10], [11]. These domains, which lack intrinsic enzymatic activity function by controlling protein–protein or protein–DNA interactions. The MH1 domain is important for mediating the DNA binding activity of Smads, as well as being

SARA, a Smad/receptor anchor protein

The first step in the TGFβ intracellular signalling cascade involves the interaction of the R-Smad with the receptor complex. Recently, a protein named SARA (for Smad Anchor for Receptor Activation) was shown to play an important role in this process [40], [41]. A Xenopus version of SARA was isolated by screening of a bacterial expression library with the carboxy-terminal MH2 domain of Smad2 and a mammalian version was subsequently identified in a human brain cDNA library [40]. These two

Structure of the Smad2 MH2 domain bound to the SARA SBD

The recent determination of the three-dimensional structure of the Smad2 MH2 domain in complex with the SARA Smad binding domain (SBD) by X-ray crystallography has provided novel insights into how Smad2 and SARA associate [36]. The first Smad crystal structure to be solved was that of the MH2 domain of the common Smad, Smad4 [35]. Analysis of the structure revealed the presence of five α-helices (termed H1 to H5) and three loops (L1, L2 and L3) that enclose a β-sandwich [35]. Analysis of the

The ubiquitin–proteasome pathway and Smads

The activity of numerous cellular proteins is controlled by selective proteolysis through the ubiquitin–proteasome pathway [46]. In the first step of this enzymatic cascade, the highly conserved 76 amino acid protein, ubiquitin, is activated and attached to an E1 (ubiquitin-activating enzyme) through a thiolester bond. The ubiquitin is then transferred to an E2 (ubiquitin-conjugating enzyme) which functions together with an E3 ligase to transfer ubiquitin to the substrate. The polyubiquitinated

Nuclear function of Smad proteins

Once in the nucleus, Smads function to target specific gene promoters. Direct binding of Smads to DNA has been described for Drosophila MAD and MEDEA as well as vertebrate Smad3 and Smad4 (reviewed in [8]). However, Smads bind DNA with low affinity and low specificity and thus Smads rely on interactions with DNA binding partners to target specific genes for transcriptional regulation. The first and most extensively characterized Smad transcriptional partners are members of the FAST (forkhead

Smads as transcriptional co-modulators

Smad proteins interact with numerous nuclear factors, including DNA binding proteins, transcriptional activators and corepressors. Through these interactions, Smads can either positively or negatively regulate activation of target genes. Thus, Smads can be considered to be transcriptional co-modulators whose activity is controlled by TGFβ superfamily members, which regulate Smad activity by inducing nuclear accumulation. In the nucleus, Smads can play either a primary or secondary role in

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