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

ABSTRACT: BUB1 (budding uninhibited by benzimidazoles-1) is required for efficient TGF-? 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-? 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-? signaling. Finally, we provide evidence that the BUB1-TGF-? signaling axis may mediate aggressive phenotypes in a variety of cancers.

SUBMITTER: Nyati S

PROVIDER: S-EPMC7057164 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Nyati Shyam S Gregg Brandon S BS Xu Jiaqi J Young Grant G Kimmel Lauren L Nyati Mukesh K MK Ray Dipankar D Speers Corey C Rehemtulla Alnawaz A

Neoplasia (New York, N.Y.) 20200303 4

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 i ...[more]

PMID: 32143140

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Project description:Skeletal malocclusions are common phenotypes in humans and have a strong influence on genetic factors. Transforming growth factor beta (TGFβ) controls numerous functions of the human body, including cell proliferation, differentiation, and migration. Thus, this study is aimed at evaluating whether genetic polymorphisms in TGFB1 and its receptor TGFBR2 are associated with mandibular retrognathism in German children and adolescents. Children and teenagers older than 8 years in the mixed or permanent dentition were included in this study. Patients with syndromes and facial trauma and patients with congenital alterations were excluded. Digital cephalometric tracings were performed using the anatomical landmarks point A, point B, sella (S), and nasion (N). Patients that have a retrognathic mandible (SNB < 78°) were selected as case group, and the patients with an orthognathic mandible (SNB = 78°- 82°) were selected as the control group. Genomic deoxyribonucleic acid (DNA) from saliva was used to evaluate four genetic polymorphisms in TGFB1 (rs1800469 and rs4803455) and TGBR2 (rs3087465 and rs764522) using real-time PCR. Chi-square or Fisher exact tests were used to compare gender, genotype, and allele distribution among groups. Genotype distribution was calculated in an additive and recessive model. Haplotype analysis was also performed. The established alpha of this study was 5%. A total of 146 patients (age ranging from 8 to 18 years) were included in this epidemiological genetic study. The genetic polymorphism rs3087465 in TGFBR2 was associated with mandibular retrognathism. Carrying the AA genotype in the rs3087465 polymorphism decreased the chance of having mandibular retrognathism (odds ratio = 0.25, confidence interval 95% = 0.06 to 0.94, p = 0.045). None of the haplotypes was associated with mandibular retrognathism (p > 0.05). In conclusion, we found that the genetic polymorphism rs3087465 in the promoter region of the TGFBR2 was associated with mandibular retrognathism in Germans.

Dataset Information

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

Publications

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

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