MTG16, and other MTG family members, may play a role in the constitutive repression of both Wnt and Notch signaling pathways. (a) Cell surface activation of Frizzled-family receptors attenuates the constitutive phosphorylation and degradation of β
-catenin in the cytoplasm. An increase in β
-catenin concentration and translocation to the nucleus convert TCF-family TFs to activators of transcription at Wnt target genes. MTG family members were shown to bind Tcf4 in vitro, and the association was abrogated in the presence of β
-catenin, lending credence to the idea that MTG family members represent one of the many corepressors employed by TCF TFs in basal, inactivated states. The specific contribution of MTG16 to this pathway is controversial, and the most recent research suggests that MTGR1 carries most of the Wnt-modulatory roles in the MTG family. (b) MTG16 also interacts strongly with the intracellular domains of all four mammalian Notch receptors (N-ICD). Similar to Wnt signaling, Notch activation induces proteolytic cleavage of the intracellular portion of the receptor and translocation to the nucleus. It then converts the CSL repressor into an activator. MTG16 interacts with CSL but is displaced by N-ICD. N-ICD also directly binds MTG16, likely inducing a conformational change that inhibits MTG16:CSL interaction. Engel et al. [32
] demonstrated a role of endogenous MTG16 in Notch-directed T-cell differentiation from HSPCs.