Abstract 1137: Bub1 is a key regulator of TGF-β signaling

Abstract

The transforming growth factor-beta (TGF-β) family of cytokines regulates many processes such as immune suppression, angiogenesis, wound healing and epithelial to mesenchymal transition (EMT. Early in tumorigenesis, when epithelial cells retain exquisite growth sensitivity to this ligand, TGF-β signaling elicits a tumor suppressing activity. However, transformed cells become refractory to TGF-β-mediated growth inhibition and acquire a phenotype wherein the intracellular signaling circuitry of the cells is altered, leading to tumorigenic and metastatic effects in response to TGF-β exposure. Although TGF-β activating pathways have been studied, the molecular participants are poorly defined. Here we identify budding uninhibited by benzimidazoles-1 (Bub1) as an integral component of canonical and non-canonical TGF-β signaling pathways, where Bub1 is required for TGFBRI-TGFBRII complex formation and activation. Bub1-depleted cells exhibited reductions in TGF-β dependent Smad2/3 phosphorylation, recruitment of Smad2/3 to the TGFBRI-II complex, PI3K/Akt and p38MAPK activation, Smad binding element driven promoter activity (SBE4-Luc), and invasion and migration. Furthermore, a targeted small molecule inhibitor of Bub1 kinase activity (2OH-BNPP1), as well as an inactive kinase mutant of Bub1, abrogated ligand mediated TGF-β signaling and phenotypic response. These studies demonstrate a role for the Bub1 kinase in mediating TGF-β dependent signaling beyond its established function in cell-cycle regulation and chromosome cohesion and uncover the underlying basis for the pleiotropic cellular response commonly observed upon activation of the pathway. Citation Format: Shyam Nyati, Katrina Schinske-Sebolt, Sethuramasundaram Pitchiaya, Katerina Chekhovskiy, Areeb Chator, Nauman Chaudhry, Joseph Dosch, Marcian E. Van Dort, Varambally, Kumar-Sinha, Nyati, Ray, Walter, Sooryanarayana Varambally, Chandan Kumar-Sinha, Mukesh K. Nyati, Dipankar Ray, Nils G. Walter, Hongtao Yu, Brian D. Ross, Alnawaz Rehemtulla. Bub1 is a key regulator of TGF-β signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1137. doi:10.1158/1538-7445.AM2014-1137

BUB1 predicts poor prognosis and immune status in liver hepatocellular carcinoma

“…Previous reports have provided evidence regarding the role of BUB1 in mediating TGFβ-dependent signalling, in addition to its established function in chromosome cohesion and cell cycle regulation (Nyati et al, 2015;Nyati et al, 2020). In LIHC, BUB1 expression was correlated with TGF-β1, TGFβ2, TGFβ3, TGFβ receptor (TGFβR) 1, SMAD2, SMAD3, and SMAD4 (p < 0.05) (Fig.…”

“…Recently, combinatorial therapy with anti-PD-L1 immune checkpoint inhibitors (ICIs) and systemic TGFβR1 inhibitors (e.g., galunisertib) or anti-TGFβ antibodies was shown to promote the in ltration of T cells into the tumour core, thereby inducing tumour regression and anti-tumour immunity (Mariathasan et al, 2018). BUB1, as a kinase, is reported to have a vital impact on TGFβ-dependent signalling (Nyati et al, 2015). BUB1 is the engine of TGFβ signalling (Moustakas, 2015).…”