Smads Activation by the TGFp Receptor

Both Smad2 and Smad3 are phosphorylated by TGF-P receptor in the C-terminal SSXS motif (Abdollah et al., 1997; Souchelnytskyi et al., 1997). At the basal state, the MH1 and MH2 domains interact intramolecularly, thus inhibiting each other's activities (Hata et al., 1997). Smad phosphorylation by receptor disrupts the intramolecular interaction (Hata et al., 1997). Smad2/3-receptor interactions are mediated by the L3 loop in the MH2 domain of Smad2/3 and L45 loop in the TGF-P type I receptor (Feng and Derynck, 1997; Chen et al., 1998; Lo et al., 1998; Huse et al., 2001).

SARA (Smad anchor for receptor activation) functions to recruit Smad2 and Smad3 to the TGF-P receptor (Tsukazaki et al., 1998). SARA contains a FYVE domain for membrane localization, a Smad binding domain (SBD) for binding to Smad2/3, and a carboxyl-terminal domain for interacting with the receptor kinase (Tsukazaki et al., 1998). At the basal state, Smad2 and Smad3 are bound by SARA (Wu et al., 2000; Moustakas and Heldin, 2002; Qin et al., 2002). Structural studies indicate that SARA binds and stabilizes monomeric forms of Smad2 and Smad3, and inhibit Smad2 and Smad3 trimerization (Moustakas and Heldin, 2002; Qin et al. 2002). This helps explain, at least in part, why overexpression of Smad3 or Smad2, which can saturate SARA, leads to transcriptional activation in the absence of TGF-P signaling. Recent studies have shown that the cytoplasmic PML (promyelocytic leukaemia) protein physically interacts with both Smad2/3 and SARA and is required for association of Smad2/3 with SARA (Lin et al., 2004). Cytoplasmic PML can also bind to the receptors. Upon TGF-P binding and activation of the receptor, Cytoplasmic PML can promote the transfer of the complex containing TGF-P receptors, SARA, Smad2/3, and probably cytoplasmic PML itself into early endosome (Lin et al., 2004). Cytoplasmic PML then seems to dissociate from the complex, followed by SARA presenting Smad2 and Smad3 for receptor recognition, and precisely positioning the phosphorylation sites of Smad2 and Smad3 in the kinase catalytic center (Tsukazaki et al., 1998; Wu et al, 2000; Moustakas and Heldin, 2002; Qin et al., 2002; Shi and Massague, 2003;

Lin et al., 2004). Phosphorylation of Smad2/3 by TGF-P receptor allows Smad2/3 to dissociate from SARA and the receptor, then associate with Smad4 and accumulate in the nucleus (Wu et al., 2000; Moustakas and Heldin, 2002; Qin et al., 2002).

In addition to SARA and cytoplasmic PML, a number of other proteins with anchoring, scaffolding or chaperone activity, such as Hgs, Disabled-2, Axin, Caveolin-1, ARIP1, GIPC, STRAP, Filamin, TRAP-1, and microtubules, can regulate the recruitment of Smad2 and Smad3 to the TGF-p receptor complex or bring Smad4 into the proximity of the receptor complex and aid in the formation of heteromeric complexes between Smad2/3 and Smad4 (Wrana, 2000; Miyazono, et al. 2001; ten Dijke, et al. 2002; Liu, 2003)

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