TβRIII independently binds type I and type II TGF-β receptors to inhibit TGF-β signaling

Tazat, Keren; Hector-Greene, Melissa; Blobe, Gerard C.; Henis, Yoav I.

doi:10.1091/mbc.e15-04-0203

Cited by 34 publications

(44 citation statements)

References 56 publications

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“…18). These data suggest that the oncogenic effect of TGFBR3 overexpression in MECA is mediated by mechanisms independent of TGF-ß signaling, which is in line with previous findings in breast cancer (43).…”

Section: Detection Of a Novel Recurrent Tgfbr3-plag1 Fusionsupporting

confidence: 92%

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Multi-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions

Dalin

Katabi

Persson

et al. 2017

Preprint

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Myoepithelial carcinoma (MECA) is an aggressive type of salivary gland cancer with largely unknown molecular features. MECA may arise de novo or result from oncogenic transformation of a pre-existing pleomorphic adenoma (MECA ex-PA). We comprehensively analyzed the molecular alterations in MECA with integrated genomic analyses. We identified a low mutational load (0.5/MB), but a high prevalence of fusion oncogenes (28/40 tumors; 70%). We found FGFR1-PLAG1 in 7 (18%) cases, and the novel TGFBR3-PLAG1 fusion in 6 (15%) cases. TGFBR3-PLAG1 was specific for MECA de novo tumors or the malignant component of MECA ex-PA, was absent in 723 other salivary gland tumors, and promoted a tumorigenic phenotype in vitro.We discovered other novel PLAG1 fusions, including ND4-PLAG1, which is an oncogenic fusion between mitochondrial and nuclear DNA. One tumor harbored an MSN-ALK fusion, which was tumorigenic in vitro, and targetable with ALK inhibitors. Certain gene fusions were predicted to result in neoantigens with high MHC binding affinity. A high number of copy number alterations was associated with poorer prognosis. Our findings indicate that MECA is a fusion-driven disease, nominate TGFBR3-PLAG1 as a hallmark of MECA, and provide a framework for future steps of diagnostic and therapeutic research in this lethal cancer.

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Section: Detection Of a Novel Recurrent Tgfbr3-plag1 Fusionsupporting

confidence: 92%

“…TGFBR3 can act as a tumor suppressor which acts negatively on TGF-ß signaling by binding to TGFBR1 and TGFBR2 separately, thereby inhibiting the TGFBR1/2 complex formation (43). On the other hand, overexpression of TGFBR3 has oncogenic potential in breast and colorectal cancer (44,45).…”

Section: Detection Of a Novel Recurrent Tgfbr3-plag1 Fusionmentioning

confidence: 99%

Multi-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions

Dalin

Katabi

Persson

et al. 2017

Preprint

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“…Nevertheless, the mechanism by which the high level of TGF-β1 exerts tumorpromoting effects remains unclear. A recent study found that TβRIII inhibited TGF-β-mediated signaling through the independent binding to TβRI and TβRII and competition with TβRI/TβRII complex formation (15). We found decreased expression of TβRIII concomitant with the elevated level of TGF-β1, as well as the role of TGF-β1 in promoting metastasis in the HCC cell lines.…”

Section: Discussionsupporting

confidence: 52%

“…Overexpression of TβRIII was found to restore TGF-β1 sensitivity in CAL-27 human oral squamous cells (14). In MDA-MB-231 human breast cancer cells, TβRIII expression inhibited Smad2/3 signaling dependent on the TβRIII cytoplasmic domain, and the independent binding of TβI/TβRII to TβRIII competed with TβI/TβRII signaling complex formation, thus inhibiting TGF-β-mediated Smad signaling (15). Importantly, the alteration of TβRIII expression level and the mediating roles have been observed in the progression of several types of cancers including breast, prostate, lung and ovarian cancer (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 94%

Decreased expression of the type III TGF-β receptor enhances metastasis and invasion in hepatocellullar carcinoma progression

Zhang

Sun

et al. 2016

Oncology Reports

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Abstract. The transforming growth factor β (TGF-β) superfamily of cytokines is multifunctional and involved in the regulation of cell growth and differentiation. TGF-β can induce an epithelial-mesenchymal transition (EMT) of both epithelial and endothelial cells. This has consequences for cancer progression in regards to both migration and invasion abilities. The type III TGF-β receptor (TβRIII) is a ubiquitously expressed TGF-β co-receptor which regulates TGF-β signaling and the progression of various types of cancer. Previous studies have shown that TβRIII exhibits abnormal expression and plays an essential role in regulating cancer invasion and metastasis, while little is known in regards to its role in hepatocellular carcinoma (HCC) progression. In the present study, we designed the present research to study the role of TβRIII in the invasion and metastasis of HCC and the possible mechanisms involved. The results demonstrated decreased expression of TβRIII in HCC patient tissues and human HCC cell lines. TGF-β1 stimulation led to the increased migratory ability and reduced expression of TβRIII in HCC cells. In addition, knockdown of TβRIII by small interfering RNA (siRNA) promoted the migration and invasion of HCC cells and induced activation of the Smad2 and Akt pathways. All the results suggest that TβRIII is a novel suppressor of HCC progression.

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“…Betaglycan has been shown to promote both Smad and non-Smad signaling (You et al 2007). However, betaglycan binds TbRI and TbRII independently, and overexpression of betaglycan in MDA-MB-231 cells was found to inhibit TGF-b-induced Smad2 and Smad3 phosphorylation (Tazat et al 2015). Betaglycan is basolaterally located in polarized breast epithelial cells, and loss of the basolateral localization promotes EMT (Meyer et al 2014).…”

Section: Betaglycan/tbriiimentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

554

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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TβRIII independently binds type I and type II TGF-β receptors to inhibit TGF-β signaling

Cited by 34 publications

References 56 publications

Multi-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions

Multi-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions

Decreased expression of the type III TGF-β receptor enhances metastasis and invasion in hepatocellullar carcinoma progression

Signaling Receptors for TGF-β Family Members

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