Smad binding codes broken by WW domain containing proteins = Desxifrant els codis d’unió a Smad de les proteïnes amb dominis WW

Abstract

Cell fate is controlled by a multitude of signals and loss of this control has devastating consequences for living organisms. One of the key players in this network of signals is the TGF-beta family of cytokines. These hormones trigger an immense amount of responses by sending activated Smad transcription factors (Sma and Mad related proteins) to the nucleus where participate in the control of stem cell pluripotency and differentiation, embryo development, tissue regeneration, and differentiated tissue homeostasis (Massagué, 1998).

According to their function, Smad proteins are classified as receptor regulated Smads (R-Smads), which include Smads 1, 5 and 8 in the BMP-driven version of the SMAD pathway, and Smads 2 and 3 in the TGF-beta/ Nodal/Activin pathways. R-Smads form complexes with the common co-activator Smad (Co-Smad) Smad4. The SMAD family also contains the two inhibitory Smads (I-Smads), Smad6 and Smad7, which provide critical negative regulation to these powerful and ubiquitous pathways.

All Smad proteins are modular (Shi and Massagué, 2003). R-Smads and the Co-Smad consist of two Mad Homology MH1 and MH2 domains connected by a linker that functions as a scaffold upon which other proteins can interact and modulate the functional outcome. This linker contains a conserved cluster of phosphorylation sites adjacent to a PY motif. MH1 domains of R-Smads and Smad4 bind to DNA, whereas the MH2 domain and the linker function as scaffolds for receptors, regulator proteins, and transcription cofactors to interact and determine the outcome of the signal (Shi and Massagué, 2003). Compared to R-Smads and Co-Smads, the I-Smads have low sequence similarity in the MH1 domain but conserve an MH2 domain and a linker region with a characteristic PY motif. The presence of the common regions facilitates the competition of R-Smads and I-Smads for the receptor and ligands and it facilitates the inhibitory role of I-Smads (Figure 1). I-Smads are expressed in response to TGF-β or BMPs to provide negative feedback in the pathway (Bai and Cao, 2002; Hata et al., 1998; He et al., 2002; Kavsak et al., 2000; Nakao et al., 1997; Yan and Chen, 2011) and in response to other pathways such as STAT to oppose TGF-β signaling (Ulloa et al., 1999). Smad6 interferes with the formation of Smad1-Smad4 complexes (Hata et al., 1998) whereas Smad7 interferes with the formation of R-Smads-Smad4 complexes and inhibits TGF-β and BMP receptors (Hayashi et al., 1997; Topper et al., 1998).

Several key phosphorylations drive the Smad signaling process. The ligand cytokines activate receptor serine/threonine protein kinases that phosphorylate Smad proteins at the C-terminus. The BMP receptors act on Smads 1, 5 and 8 and the receptors for the TGF-beta /nodal/activin/myostatin group of ligands act mainly on Smads 2 and 3 (Shi and Massagué, 2003). The phosphorylated C-terminus provides a binding site for Smad4, which is an essential component in the assembly of target-specific transcriptional complexes. These phosphorylations are reversed by protein phosphatases that limit the general pool of activated Smad molecules (Inman et al., 2002; Lin et al., 2006; Schmierer et al., 2008; Xu et al., 2002).