TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling.

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

Neoplasia

authors

Nyati S,Gregg BS,Xu J,Young G,Kimmel L,Nyati MK,Ray D,Speers C,Rehemtulla A

doi

10.1016/j.neo.2020.02.001

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

163-178

issue

4

eissn

1522-8002

issn

1476-5586

pii

S1476-5586(20)30009-9

journal_volume

22

pub_type

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