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

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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

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Benzimidazoles
Transforming Growth Factors
Phosphotransferases
Neoplasms
Bearings (structural)
Cells
Phosphorylation
Epithelial-Mesenchymal Transition
Growth Factor Receptors
Cell proliferation
p38 Mitogen-Activated Protein Kinases
Transcription
Chromosomes
RNA Interference
Heterografts
Tumors
Cell Differentiation
Cell Cycle
Transcription Factors
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Nyati, S., Schinske-Sebolt, K., Pitchiaya, S., Chekhovskiy, K., Chator, A., Chaudhry, N., ... 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

Cancer : The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling. / Nyati, Shyam; Schinske-Sebolt, Katrina; Pitchiaya, Sethuramasundaram; Chekhovskiy, Katerina; Chator, Areeb; Chaudhry, Nauman; Dosch, Joseph; Van Dort, Marcian E.; Varambally, Sooryanarayana; Kumar-Sinha, Chandan; Nyati, Mukesh Kumar; Ray, Dipankar; Walter, Nils G.; Yu, Hongtao; Ross, Brian Dale; Rehemtulla, Alnawaz.

In: Science Signaling, Vol. 8, No. 358, ra1, 06.01.2015.

Research output: Contribution to journalArticle

Nyati, S, Schinske-Sebolt, K, Pitchiaya, S, Chekhovskiy, K, Chator, A, Chaudhry, N, Dosch, J, Van Dort, ME, Varambally, S, Kumar-Sinha, C, Nyati, MK, Ray, D, Walter, NG, Yu, H, Ross, BD & Rehemtulla, A 2015, 'Cancer: The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling', Science Signaling, vol. 8, no. 358, ra1. https://doi.org/10.1126/scisignal.2005379
Nyati S, Schinske-Sebolt K, Pitchiaya S, Chekhovskiy K, Chator A, Chaudhry N et al. Cancer: The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling. Science Signaling. 2015 Jan 6;8(358). ra1. https://doi.org/10.1126/scisignal.2005379
Nyati, Shyam ; Schinske-Sebolt, Katrina ; Pitchiaya, Sethuramasundaram ; Chekhovskiy, Katerina ; Chator, Areeb ; Chaudhry, Nauman ; Dosch, Joseph ; Van Dort, Marcian E. ; Varambally, Sooryanarayana ; Kumar-Sinha, Chandan ; Nyati, Mukesh Kumar ; Ray, Dipankar ; Walter, Nils G. ; Yu, Hongtao ; Ross, Brian Dale ; Rehemtulla, Alnawaz. / Cancer : The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling. In: Science Signaling. 2015 ; Vol. 8, No. 358.
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