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MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth

Journal of Molecular Cell Biology 2018年第3期10卷 195-204页

作者： Rachel Xi-Yeen Ho Rosana D. Meyer Kevin B. Chandler esma ersoy Michael Park Philip A. Bondzie Nima Rahimi Huihong Xu Catherine E. Costello Nader Rahimi Department of Pathology School of Medicine Boston University Medical Campus Boston MA 02118 USA Department of Biochemistry and Center for Biomedical Mass Spectrometry School of Medicine Boston University Medical Campus Boston MA 02118 USA

Intrinsically disordered proteins （IDPs）/intrinsicaUy unstructured proteins are characterized by the lack of fixed or stable tertiary structure, and are increasingly recognized as an important class of proteins with major roles in signal transduction and transcriptional regulation. In this study, we report the identification and functional characterization of a previously uncharacterized protein （UPFO258/KIAA1024）, major intrinsically disordered Notch2-associated receptor 1 （MINAR1）. While MINAR1 carries a single transmembrane domain and a short cytoplasmic domain, it has a large extraceUular domain that shares no similarity with known protein sequences. Uncharacteristically, MINAR1 is a highly IDP with nearly 70% of its amino acids sequences unstructured. We demonstrate that MINAR1 physically interacts with Notch2 and its binding to Notch2 increases its stability and function. MINAR1 is widely expressed in various tissues including the epithelial cells of the breast and endothelial cells of blood vessels. MINAR1 plays a negative role in angioganesis as it inhibits angioganesis in cell culture and in mouse matrigal plug and zebraflsh anglo- genesis models. Furthermore, while MINAR1 is highly expressed in the normal human breast, its expression is significantly down- regulated in advanced human breast cancer and its re-expression in breast cancer cells inhibited tumor growth. Our study demonstrates that MINAR1 is an IDP that negatively regulates angioganesis and growth of breast cancer cells.

关键词： intrinsically disordered proteins Notch2 angiogenesis breast cancer MINAR1

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