I-SMAD competes with SMAD2/3 for type I receptor (TGFBR1)

I-SMADs (SMAD6 and SMAD7) reside in the nucleus presumably to be sequestered from the TGF-beta receptor complex and thus avoid inappropriate silencing of the signaling pathway. Upon activation of the signaling pathway, I-SMADs exit the nucleus and are recruited to the signaling TGF-beta receptor complex. I-SMADs directly bind to the so-called L45 loop of the type I receptor, the site of binding of R-SMADs. Thus, I-SMADs competitively inhibit the activation/phosphorylation of R-SMADs.

I-SMADs（SMAD6和SMAD7）位于细胞核内，推测其目的是为了避免被TGF-β受体复合物隔离，从而避免信号通路的不当沉默。在信号通路的激活过程中，I-SMADs脱离细胞核，并被招募至TGF-β受体信号复合物。I-SMADs可直接与I型受体的所谓L45环结合，这是R-SMADs的结合位点。因此，I-SMADs可竞争性地抑制R-SMADs的激活/磷酸化。