Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein.

By Bin Zhao, Li Li, Qing-jun Lu, Lloyd H. Wang, Chenying Liu, Q. Lei, K. Guan. Genes & Development, 2011

694 citations recorded by the source corpus.

The Yes-associated protein (YAP) is a transcription coactivator that plays a crucial role in organ size control by promoting cell proliferation and inhibiting apoptosis. The Hippo tumor suppressor pathway inhibits YAP through phosphorylation-induced cytoplasmic retention and degradation. Here we report a novel mechanism of YAP regulation by angiomotin (AMOT) family proteins via a direct interaction. Knockdown of AMOT family protein AMOTL2 in polarized Madin-Darby canine kidney (MDCK) cells leads to YAP activation, as indicated by decreased YAP tight junction localization, attenuated YAP phosphorylation, accumulation of nuclear YAP, and induction of YAP target gene expression. Transcriptional coactivator with PDZ-binding motif (TAZ), the YAP paralog, is also regulated by AMOT in a similar fashion. Furthermore, AMOTL2 knockdown results in loss of cell contact inhibition in a manner dependent on the functions of YAP and TAZ. Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition.

Subfields: Cell Biology

View Paper: https://www.semanticscholar.org/paper/a8583dfd2967dc9257b2cca0f7906caef8b56d2b

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In Cell Biology

1. K. Guan
2. S. Piccolo
3. Fa-Xing Yu
4. M. Cordenonsi
5. Bin Zhao
6. H. Park
7. Jung-Soon Mo
8. S. Dupont

Citations in the corpus

• Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. (2012, background): “We recently reported that the angiomotin family proteins could mediate YAP localization to tight junctions and the actin cytoskeleton and promote YAP phosphorylation (Zhao et al. 2011).”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “Initial reports supported an inhibitory role for AMOTs as factors promoting either the sequestration of YAP/TAZ (25, 163, 220, 263) or the activation of the Hippo pathway (1, 86).”
• The Hippo pathway: regulators and regulations. (2013, background): “The AMOT–YAP/TAZ interaction is not dependent on the YAP/TAZ phosphorylation status and is instead mediated by AMOT PPxY motifs and YAP/ TAZ WW domains (Chan et al. 2011; Wang et al. 2011; Zhao et al. 2011).”
• The Hippo signaling pathway in stem cell biology and cancer (2014, positive): “It should be noted that there is strong evidence supporting that angiomotin mediates cell–cell contact and tight junction signals to inhibit YAP function by both increasing YAP phosphorylation and physical binding [78,104].”
• Hippo pathway regulation by cell morphology and stress fibers (2011, background): “, 2010), Angiomotin (Chan et al., 2011; Wang et al., 2010; Zhao et al., 2011) and -catenin (Schlegelmilch et al.”
• The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease (2014, background): “Angiomotin (AMOT), a factor that is recruited to the Crumbs complex in epithelial cells (Wells et al., 2006), also tightly associates with TAZ/YAP (Varelas et al., 2010b; Wang et al., 2011; Zhao et al., 2011).”