Cancer: The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling

Shyam Nyati, Katrina Schinske-Sebolt, Sethuramasundaram Pitchiaya, Katerina Chekhovskiy, Areeb Chator, Nauman Chaudhry, Joseph Dosch, Marcian E. Van Dort, Sooryanarayana Varambally, Chandan Kumar-Sinha, Mukesh Kumar Nyati, Dipankar Ray, Nils G. Walter, Hongtao Yu, Brian Dale Ross, Alnawaz Rehemtulla

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) signaling regulates cell proliferation and differentiation, which contributes to development and disease. Upon binding TGF-β, the type I receptor (TGFBRI) binds TGFBRII, leading to the activation of the transcription factors SMAD2 and SMAD3. Using an RNA interference screen of the human kinome and a live-cell reporter for TGFBR activity, we identified the kinase BUB1 (budding uninhibited by benzimidazoles-1) as a key mediator of TGF-β signaling. BUB1 interacted with TGFBRI in the presence of TGF-β and promoted the heterodimerization of TGFBRI and TGFBRII. Additionally, BUB1 interacted with TGFBRII, suggesting the formation of a ternary complex. Knocking down BUB1 prevented the recruitment of SMAD3 to the receptor complex, the phosphorylation of SMAD2 and SMAD3 and their interaction with SMAD4, SMAD-dependent transcription, and TGF-β-mediated changes in cellular phenotype including epithelial-mesenchymal transition (EMT), migration, and invasion. Knockdown of BUB1 also impaired noncanonical TGF-β signaling mediated by the kinases AKT and p38 MAPK (mitogen-activated protein kinase). The ability of BUB1 to promote TGF-β signaling depended on the kinase activity of BUB1. A small-molecule inhibitor of the kinase activity of BUB1 (2OH-BNPP1) and a kinase-deficient mutant of BUB1 suppressed TGF-β signaling and formation of the ternary complex in various normal and cancer cell lines. 2OH-BNPP1 administration to mice bearing lung carcinoma xenografts reduced the amount of phosphorylated SMAD2 in tumor tissue. These findings indicated that BUB1 functions as a kinase in the TGF-β pathway in a role beyond its established function in cell cycle regulation and chromosome cohesion.

Original languageEnglish (US)
Article numberra1
JournalScience Signaling
Volume8
Issue number358
DOIs
StatePublished - Jan 6 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Nyati, S., Schinske-Sebolt, K., Pitchiaya, S., Chekhovskiy, K., Chator, A., Chaudhry, N., Dosch, J., Van Dort, M. E., Varambally, S., Kumar-Sinha, C., Nyati, M. K., Ray, D., Walter, N. G., Yu, H., Ross, B. D., & Rehemtulla, A. (2015). Cancer: The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling. Science Signaling, 8(358), [ra1]. https://doi.org/10.1126/scisignal.2005379