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bioRxiv · 10.1101/2021.09.29.462397

The YAP/TAZ antagonist, PTPN14, stabilizes SMAD4 through direct interactions in endothelial cells: Implications for Hereditary Hemorrhagic Telangiectasia

MAMAI, O.·Beleford, D.·Taylor, M.·Basu, S.·Cen, X.·Trilok, S.·Zhang, J.·Balmain, A.·Akhurst, R.
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Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) results from germline loss-of-function mutations of ENG, ACVRL1, or SMAD4, encoding TGF{beta}/BMP signaling components. Telangiectasias occur in most patients, and pulmonary, visceral, or cerebral arteriovenous malformations (AVMs) in 20-50% of these. How HHT mutations cause these clinical manifestations and why some patients suffer more serious sequelae than others is unknown. PTPN14 is a genetic modifier of pulmonary AVM incidence, and here we show by gene expression network analysis of a large panel of genetically diverse mouse lung RNA samples, that Ptpn14 is ontologically associated with markers of angiogenesis, vascular remodeling, and BMP/TGF{beta} and Rho kinase signaling. We demonstrate physical interaction between protein tyrosine phosphatase non-receptor, type 14 (PTPN14) and SMAD4 in nucleus and cytoplasm of primary human endothelial cells. PTPN14 suppresses ubiquitination and turnover of SMAD4 to augment tonic SMAD-mediated transcriptional readouts. This is the first report that PTPN14 binds and stabilizes SMAD4, a key component of the HHT signaling pathway. Through this mechanism, and its inhibition of YAP/TAZ signaling, PTPN14 levels may protect against development of AVMs in HHT. We discuss potential druggable targets for HHT within the ENG-ALK1-SMAD4-PTPN14 network. One Sentence SummaryPTPN14 binds and stabilizes SMAD4 to potentiate BMP9 signaling in endothelial cells and components of the PTPN14 network may be drug targets for HHT.

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MAMAI, O., Beleford, D., Taylor, M., Basu, S., Cen, X., Trilok, S., Zhang, J., Balmain, A., Akhurst, R.. 2021-09-30. The YAP/TAZ antagonist, PTPN14, stabilizes SMAD4 through direct interactions in endothelial cells: Implications for Hereditary Hemorrhagic Telangiectasia. https://doi.org/10.1101/2021.09.29.462397

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