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Abstract
SummaryAberrant WNT signaling drives colorectal cancer (CRC). Here, we identify TIAM1 as a critical antagonist of CRC progression through inhibiting TAZ and YAP, effectors of WNT signaling. We demonstrate that TIAM1 shuttles between the cytoplasm and nucleus antagonizing TAZ/YAP by distinct mechanisms in the two compartments. In the cytoplasm, TIAM1 localizes to the destruction complex and promotes TAZ degradation by enhancing its interaction with βTrCP. Nuclear TIAM1 suppresses TAZ/YAP interaction with TEADs, inhibiting expression of TAZ/YAP target genes implicated in epithelial-mesenchymal transition, cell migration, and invasion, and consequently suppresses CRC cell migration and invasion. Importantly, high nuclear TIAM1 in clinical specimens associates with increased CRC patient survival. Together, our findings suggest that in CRC TIAM1 suppresses tumor progression by regulating YAP/TAZ activity.
Highlights
Intestinal epithelial cells transform into malignant cells following mutations in various oncogenes and tumor suppressors that drive changes in programs of gene expression
Nuclear TIAM1 Expression in Human Tumors is a Prognostic Marker for colorectal cancer (CRC) Progression Previously, using recombinant mouse models, we have shown that TIAM1 cooperates with WNT signaling during initiation of intestinal epithelial neoplasia but appeared to antagonize tumor progression (Malliri et al, 2006)
TIAM1 cytoplasmic staining decreased with advancing Dukes stage (c2 = 19.057, p = 0.001) (Figures 1A and S1B)
Summary
Intestinal epithelial cells transform into malignant cells following mutations in various oncogenes and tumor suppressors that drive changes in programs of gene expression. The initiating event is inactivation of the tumor suppressor adenomatous polyposis coli (APC) or, less frequently, activation of b-catenin, resulting in constitutive activation of the canonical WNT pathway. At the core of this pathway is the regulation of b-catenin by a cytoplasmic destruction complex. In the absence of a WNT signal, the central scaffold protein AXIN within the destruction complex binds APC which efficiently delivers cytosolic b-catenin to be phosphorylated by CK1 and GSK3b. Phosphorylated b-catenin is subsequently ubiquitylated by the E3 ligase bTrCP and degraded by the proteasome. Binding of WNT to its receptor causes inactivation of the destruction complex, stabilization, and nuclear translocation of b-catenin, and subsequent transcription by a b-catenin/TCF complex (Clevers, 2006)
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