TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling
BUB1 (budding uninhibited by benzimidazoles-1) is required for efficient TGF-β signaling, through its role in stabilizing the TGFBR1 and TGFBR2 complex. Here we demonstrate that TGFBR2 phosphorylates BUB1 at Serine-318, which is conserved in primates. S318 phosphorylation abrogates the interaction o...
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Series: | Neoplasia: An International Journal for Oncology Research |
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doaj-15ddb17817d04f17a196bc1e17d92b722020-11-24T21:54:18ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862020-04-01224163178TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signalingShyam Nyati0Brandon S. Gregg1Jiaqi Xu2Grant Young3Lauren Kimmel4Mukesh K. Nyati5Dipankar Ray6Corey Speers7Alnawaz Rehemtulla8Corresponding authors. Department of Radiation Oncology, University of Michigan, 1301 Catherine Road, Med Sci I, #4433D, Ann Arbor, MI-48109-5637, USA (S. Nyati); Department of Radiation Oncology, University of Michigan, 1600 Huron Parkway, NCRC, #520, Ann Arbor, MI-48109. USA (A. Rehemtulla).; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USACorresponding authors. Department of Radiation Oncology, University of Michigan, 1301 Catherine Road, Med Sci I, #4433D, Ann Arbor, MI-48109-5637, USA (S. Nyati); Department of Radiation Oncology, University of Michigan, 1600 Huron Parkway, NCRC, #520, Ann Arbor, MI-48109. USA (A. Rehemtulla).; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USABUB1 (budding uninhibited by benzimidazoles-1) is required for efficient TGF-β signaling, through its role in stabilizing the TGFBR1 and TGFBR2 complex. Here we demonstrate that TGFBR2 phosphorylates BUB1 at Serine-318, which is conserved in primates. S318 phosphorylation abrogates the interaction of BUB1 with TGFBR1 and SMAD2. Using BUB1 truncation domains (1–241, 241–482 and 482–723), we demonstrate that multiple contact points exist between BUB1 and TGF-β signaling components and that these interactions are independent of the BUB1 tetratricopeptide repeat (TPR) domain. Moreover, substitutions in the middle domain (241–482) encompassing S318 reveals that efficient interaction with TGFBR2 occurs only in its dephosphorylated state (241–482 S318A). In contrast, the phospho-mimicking mutant (241–482 S318D) exhibits efficient binding with SMAD2 and its over-expression results in a decrease in TGFBR1-TGFBR2 and TGFBR1-SMAD2 interactions. These findings suggest that TGFBR2 mediated BUB1 phosphorylation at S318 may serve as a switch for the dissociation of the SMAD2-TGFBR complex, and therefore represents a regulatory event for TGF-β signaling. Finally, we provide evidence that the BUB1-TGF-β signaling axis may mediate aggressive phenotypes in a variety of cancers. Keywords: BUB1 (budding uninhibited by benzimidazoles-1), kinase, TGFb (transforming growth factor-beta), SMAD2, SMAD3, TGFBR1, TGFBR2, signaling, phosphorylation, regulationhttp://www.sciencedirect.com/science/article/pii/S1476558620300099 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shyam Nyati Brandon S. Gregg Jiaqi Xu Grant Young Lauren Kimmel Mukesh K. Nyati Dipankar Ray Corey Speers Alnawaz Rehemtulla |
spellingShingle |
Shyam Nyati Brandon S. Gregg Jiaqi Xu Grant Young Lauren Kimmel Mukesh K. Nyati Dipankar Ray Corey Speers Alnawaz Rehemtulla TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling Neoplasia: An International Journal for Oncology Research |
author_facet |
Shyam Nyati Brandon S. Gregg Jiaqi Xu Grant Young Lauren Kimmel Mukesh K. Nyati Dipankar Ray Corey Speers Alnawaz Rehemtulla |
author_sort |
Shyam Nyati |
title |
TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling |
title_short |
TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling |
title_full |
TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling |
title_fullStr |
TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling |
title_full_unstemmed |
TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling |
title_sort |
tgfbr2 mediated phosphorylation of bub1 at ser-318 is required for transforming growth factor-β signaling |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 |
publishDate |
2020-04-01 |
description |
BUB1 (budding uninhibited by benzimidazoles-1) is required for efficient TGF-β signaling, through its role in stabilizing the TGFBR1 and TGFBR2 complex. Here we demonstrate that TGFBR2 phosphorylates BUB1 at Serine-318, which is conserved in primates. S318 phosphorylation abrogates the interaction of BUB1 with TGFBR1 and SMAD2. Using BUB1 truncation domains (1–241, 241–482 and 482–723), we demonstrate that multiple contact points exist between BUB1 and TGF-β signaling components and that these interactions are independent of the BUB1 tetratricopeptide repeat (TPR) domain. Moreover, substitutions in the middle domain (241–482) encompassing S318 reveals that efficient interaction with TGFBR2 occurs only in its dephosphorylated state (241–482 S318A). In contrast, the phospho-mimicking mutant (241–482 S318D) exhibits efficient binding with SMAD2 and its over-expression results in a decrease in TGFBR1-TGFBR2 and TGFBR1-SMAD2 interactions. These findings suggest that TGFBR2 mediated BUB1 phosphorylation at S318 may serve as a switch for the dissociation of the SMAD2-TGFBR complex, and therefore represents a regulatory event for TGF-β signaling. Finally, we provide evidence that the BUB1-TGF-β signaling axis may mediate aggressive phenotypes in a variety of cancers. Keywords: BUB1 (budding uninhibited by benzimidazoles-1), kinase, TGFb (transforming growth factor-beta), SMAD2, SMAD3, TGFBR1, TGFBR2, signaling, phosphorylation, regulation |
url |
http://www.sciencedirect.com/science/article/pii/S1476558620300099 |
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