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Sci. Signal., 3 September 2013
Vol. 6, Issue 291, p. ra77
[DOI: 10.1126/scisignal.2004060]


The p130 Isoform of Angiomotin Is Required for Yap-Mediated Hepatic Epithelial Cell Proliferation and Tumorigenesis

Chunling Yi1*{dagger}, Zhewei Shen2*, Anat Stemmer-Rachamimov3, Noor Dawany4, Scott Troutman5, Louise C. Showe4, Qin Liu4, Akihiko Shimono6, Marius Sudol7,8, Lars Holmgren9, Ben Z. Stanger2{dagger}, and Joseph L. Kissil5{dagger}

1 Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
2 Gastroenterology Division, Department of Medicine, Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
4 Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
5 Department of Cancer Biology, The Scripps Institute, Jupiter, FL 33458, USA.
6 TransGenic Inc., 7-1-14 Minatojima-minami, Chuo, Kobe 650-0047, Japan.
7 Weis Center for Research, Geisinger Clinic, Danville, PA 17821, USA.
8 Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
9 Department of Oncology and Pathology, Karolinska Institutet Stockholm, SE 17176 Stockholm, Sweden.

* These authors contributed equally to this work.

Abstract: The Hippo-Yap signaling pathway regulates a number of developmental and adult cellular processes, including cell fate determination, tissue growth, and tumorigenesis. Members of the scaffold protein angiomotin (Amot) family interact with several Hippo pathway components, including Yap (Yes-associated protein), and either stimulate or inhibit Yap activity. We used a combination of genetic, biochemical, and transcriptional approaches to assess the functional consequences of the Amot-Yap interaction in mice and in human cells. Mice with a liver-specific Amot knockout exhibited reduced hepatic "oval cell" proliferation and tumorigenesis in response to toxin-induced injury or when crossed with mice lacking the tumor suppressor Nf2. Biochemical examination of the Amot-Yap interaction revealed that the p130 splicing isoform of Amot (Amot-p130) and Yap interacted in both the cytoplasm and nucleus, which involved binding of PPxY and LPxY motifs in Amot-p130 to WW domains of Yap. In the cytoplasm, Amot-p130 prevented the phosphorylation of Yap by blocking access of the WW domains to the kinase Lats1. Within the nucleus, Amot-p130 was associated with the transcriptional complex containing Yap and Teads (TEA domain family members) and contributed to the regulation of a subset of Yap target genes, many of which are associated with tumorigenesis. These findings indicated that Amot acts as a Yap cofactor, preventing Yap phosphorylation and augmenting its activity toward a specific set of genes that facilitate tumorigenesis.

{dagger} Corresponding author. E-mail: jkissil{at} (J.L.K.); bstanger{at} (B.Z.S.); cy232{at} (C.Y.)

Citation: C. Yi, Z. Shen, A. Stemmer-Rachamimov, N. Dawany, S. Troutman, L. C. Showe, Q. Liu, A. Shimono, M. Sudol, L. Holmgren, B. Z. Stanger, J. L. Kissil, The p130 Isoform of Angiomotin Is Required for Yap-Mediated Hepatic Epithelial Cell Proliferation and Tumorigenesis. Sci. Signal. 6, ra77 (2013).

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