A new study entitled “The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling” discovered a key mediator of TGF-β signaling in tumors, the kinase BUB1. The study was published in the journal Science Signaling.
TGF-β, short for transforming growth factor–β, regulates cell proliferation and differentiation by binding to its receptor, the Transforming Growth Factor-Beta Receptor (TGFBR), composed by a type I and type II receptor, and activating SMAD2 and SMAD3 transcription factors. Thus, while its activity is important during development it also impacts disease progression, particularly in cancer. However, TGF-β was previously shown not only to suppress but also promote tumorigenesis.
In this study, a team of researchers at the University of Michigan Comprehensive Cancer Center aimed to identify the proteins that regulate the activity of type I TGF-b receptor (TGFBRI) in cancer cell lines. To this end, the authors performed a knock-down strategy with small interfering RNAs (siRNAs) against 720 kinases, in both lung adenocarcinoma and breast cancer cell lines, with each cell line reporting TGFBRI kinase activity.
The authors searched for hits that appeared in both cell lines and discovered a new kinase that has never been associated with TGF-β signaling – the kinase BUB1 (short for budding uninhibited by benzimidazoles-1). They performed functional studies and discovered that BUB1 is important in the formation of the TGFBR complex (I/II), key for the activation of downstream signaling cascade. Thus, BUB1 is a key regulator of TGF-β signaling.
Accordingly, knocking-down BUB1 prevented the recruitment of many key factors leading to the shut-down of the TGF-β pathway. Notably, with BUB1 knockdown the researchers prevented the tumorigenic potential of TGF-β, observed by loss of cells’ epithelial-mesenchymal transition (EMT), migration, and invasion. Additionally, the authors used a specific BUB1 inhibitor, 2OH-BNPP1, in mice with lung carcinoma xenografts and observed a decreased activation of SMAD2, a mediator of TGF-β signaling.
Thus, researchers highlight that their results open new avenues for the development of future therapies targeting TGF-β signaling.
Alnawaz Rehemtulla, Ph.D., Ruth Tuttle Freeman Research Professor of radiation oncology and radiology, co-director of the Center for Molecular Imaging at the University of Michigan Medical School and study leading author commented on a recent press release, “When you look at gene expression in cancer, Bub1 is in the top five. In addition, Bub1 expression levels correlate with outcome in patients with lung and breast cancer. But we never knew why. Now that we have that link, we’re a step closer to shutting down this cycle.”