The Tumor Suppressor SCRIB is a Negative Modulator of the Wnt/ß-Catenin Signaling Pathway.

ABSTRACT

SCRIB is a scaffold protein containing leucine-rich repeats (LRR) and PSD-95/Dlg-A/ZO-1 domains (PDZ) that localizes at the basolateral membranes of polarized epithelial cells. Deregulation of its expression or localization leads to epithelial defects and tumorigenesis in part as a consequence of its repressive role on several signaling pathways including AKT, ERK, and HIPPO. In the present work, a proteomic approach is used to characterize the protein complexes associated to SCRIB and its paralogue LANO. Common and specific sets of proteins associated to SCRIB and LANO by MS are identified and an extensive landscape of their associated networks and the first comparative analysis of their respective interactomes are provided. Under proteasome inhibition, it is further found that SCRIB is associated to the ß-catenin destruction complex that is central in Wnt/ß-catenin signaling, a conserved pathway regulating embryonic development and cancer progression. It is shown that the SCRIB/ß-catenin interaction is potentiated upon Wnt3a stimulation and that SCRIB plays a repressing role on Wnt signaling. The data thus provide evidence for the importance of SCRIB in the regulation of the Wnt/ß-catenin pathway.