Accepted for publication (PostPrint)
The Notch signaling pathway governs many distinct cellular processes by regulating transcriptional programs. The transcriptional response initiated by Notch is highly cell context dependent, indicating that multiple factors influence Notch target gene selection and activity. However, the mechanism by which Notch drives target gene transcription is not well understood. Herein, we identify and characterize a novel Notch-interacting protein, Notch activation complex kinase (NACK), which acts as a Notch transcriptional coactivator. We show that NACK associates with the Notch transcriptional activation complex on DNA, mediates Notch transcriptional activity, and is required for Notch-mediated tumorigenesis. We demonstrate that Notch1 and NACK are coexpressed during mouse development and that homozygous loss of NACK is embryonic lethal. Finally, we show that NACK is also a Notch target gene, establishing a feed-forward loop. Thus, our data indicate that NACK is a key component of the Notch transcriptional complex and is an essential regulator of Notch-mediated tumorigenesis and development.
Weaver, Kelly L; Alves-Guerra, Marie-Clotilde; Jin, Ke; Wang, Zhiqiang; Han, Xiaoqing; Ranganathan, Prathibha; Zhu, Xiaoxia; DaSilva, Thiago; Liu, Wei; Ratti, Francesca; Demarest, Renee M; Tzimas, Cristos; Rice, Meghan; Vasquez-Del Carpio, Rodrigo; Dahmane, Nadia; Robbins, David J; and Capobianco, Anthony J, "NACK Is an Integral Component of the Notch Transcriptional Activation Complex and Is Critical for Development and Tumorigenesis" (2014). School of Osteopathic Medicine Faculty Scholarship. 93.
Weaver KL, Alves-Guerra MC, Jin K, Wang Z, Han X, Ranganathan P, Zhu X, DaSilva T, Liu W, Ratti F, Demarest RM, Tzimas C, Rice M, Vasquez-Del Carpio R, Dahmane N, Robbins DJ, Capobianco AJ. NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis. Cancer Research. 2014 Sep 1;74(17):4741-51. Epub 2014 Jul 18. doi: 10.1158/0008-5472.CAN-14-1547. PMID: 25038227; PMCID: PMC4154994.