SnoN in regulation of embryonic development and tissue morphogenesis

Abstract

SnoN (Ski-novel protein) plays an important role in embryonic development, tumorigenesis and aging. Past studies largely focused on its roles in tumorigenesis. Recent studies of its expression patterns and functions in mouse models and mammalian cells have revealed that SnoN interacts with multiple signaling molecules at different cellular levels to modulate the activities of several signaling pathways in a tissue context and developmental stage dependent manner. These studies suggest that SnoN may have broad functions in the embryonic development and tissue morphogenesis.

Fig. 1

Domain structure and signaling activities of SnoN. SnoN is a protein of 684 amino acids residues with a conserved ski-homology domain (green), that contains the R-Smad-binding site (blue), a SAND (Sp100, AIRE1, NucP41/75, and DEAF1)-like domain (red) that mediates binding to Smad4. The p53 and PML binding regions are indicated by the arrowheads. Upon induction, SnoN can bind to the Smad proteins to antagonize the cytostatic activity of TGF-β. Upon induction by cellular stress signals, high levels of SnoN can be recruited to the PML nuclear bodies, where it interacts with p53, leading to its stabilization and activation. This ability to induce p53-dependent senescence and apoptosis responses underlies its anti-tumorigenic activity and its ability to promote aging. In the mammary gland, SnoN is induced by TGF-β and prolactin in a synergistic manner. The elevated SnoN enhances STAT5 stability, thereby sharply increasing the activity of prolactin signaling to trigger the onset of lactation.

Fig. 2

SnoN signaling in endothelial cells. SnoN plays a key role in angiogenesis through regulating the balance of two branches of TGF-β signaling in endothelial cells. SnoN enhances activation of Smad1/5 by ALK1 while represses the activity of the ALK5 branch, thus promoting endothelial cell proliferation and migration. Q. Zhu, K. Luo / FEBS Letters 586 (2012) 1971–1976 1973