Abstract:
: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.
journal_name
Neoplasiajournal_title
Neoplasia (New York, N.Y.)authors
Nyati S,Gregg BS,Xu J,Young G,Kimmel L,Nyati MK,Ray D,Speers C,Rehemtulla Adoi
10.1016/j.neo.2020.02.001subject
Has Abstractpub_date
2020-04-01 00:00:00pages
163-178issue
4eissn
1522-8002issn
1476-5586pii
S1476-5586(20)30009-9journal_volume
22pub_type
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