The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

Mythreye, Karthikeyan; Blobe, Gerard C.

doi:10.1073/pnas.0812879106

Cited by 128 publications

(145 citation statements)

References 38 publications

(74 reference statements)

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“…During coronary vessel development, TGFβR3 is dynamically regulated and is required; TGFβR3‐null mice cannot survive after embryonic day 14.5 21. In addition, β‐arrestin2 promotes the endocytosis of TGFβR3, and TGFβR3 and β‐arrestin2 coordinately function to regulate epithelial and cancer cell migration 22. Interestingly, TGFβR3 expression is significantly suppressed in rat lungs during long‐term anoxia (day 14) 23.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Sun

Duan

et al. 2017

JAHA

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BackgroundMyocardial infarction (MI) is often accompanied by cardiomyocyte apoptosis, which decreases heart function and leads to an increased risk of heart failure. The aim of this study was to examine the effects of transforming growth factor‐β receptor III (TGFβR3) on cardiomyocyte apoptosis during MI.Methods and ResultsAn MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFβR3, and mitogen‐activated protein kinase signaling were assessed by methylthiazolyldiphenyl‐tetrazolium bromide assay, terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling assay, immunofluorescence, electron microscopy, and Western blotting. Our results demonstrated that TGFβR3 expression in the border region of the heart was dynamically changed during MI. After stimulation with H2O2, TGFβR3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFβR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGFβR3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGFβR3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFβR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGFβR3 by adeno‐associated viral vector serotype 9–TGFβR3 short hairpin RNA attenuated the effects of MI in mice.Conclusions TGFβR3 promotes apoptosis of cardiomyocytes via a p38 pathway–associated mechanism, and loss of TGFβR3 reduces MI injury, which suggests that TGFβR3 may serve as a novel therapeutic target for MI.

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Sun

Duan

et al. 2017

JAHA

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“…First, endoglin shares sequence similarity with the other TGF-b co-receptor betaglycan (also known as TGF-b receptor III). Betaglycan can also inhibit cell migration independently of TGF-b and its receptors, and instead associates directly with b-arrestin (Mythreye and Blobe, 2009). Here we observed that endoglin expression modulates focal adhesion formation and turnover.…”

Section: Discussionmentioning

confidence: 99%

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

et al. 2010

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Tumor growth factor-b (TGF-b) signaling in cancer has been implicated in growth suppression of early lesions and enhancing tumor cell invasion and metastasis. However, the cellular mechanisms that determine this signaling output in individual tumors are still largely unknown. In endothelial cells, TGF-b signaling is modulated by the TGF-b coreceptor endoglin (CD105). Here we demonstrate that endoglin is expressed in a subset of invasive breast cancers and cell lines and is subject to epigenetic silencing by gene methylation. Endoglin downregulation in non-tumorigenic MCF10A breast cells leads to the formation of abnormal acini in 3D culture, but does not promote cell migration or transformation. In contrast, in the presence of activated ErbB2, endoglin downregulation in MCF10A cells leads to enhanced invasion into a 3D matrix. Consistent with these data, ectopic expression of endoglin in MDA-MB-231 cells blocks TGF-b-enhanced cell motility and invasion and reduces lung colonization in an in vivo metastasis model. Unlike endothelial cells, endoglin does not modulate Smadmediated TGF-b signaling in breast cells but attenuates the cytoskeletal remodeling to impair cell migration and invasion. Importantly, in a large cohort of invasive breast cancers, lack of endoglin expression in the tumor cell compartment correlates with ENG gene methylation and poor clinical outcome.

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“…Loss of TBR3 expression has been reported in multiple cancers, with loss of expression correlating with progression and worse prognosis (Dong et al 2007;Gatza et al 2010;Mythreye and Blobe 2009;Hanks et al 2013;Gordon et al 2008). In breast cancer, TBR3 inhibits cell migration and invasion, supporting a tumor suppressor function (Dong et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Characterization of type III TGF‐β receptor expression in invasive breast carcinomas: a potential new marker and target for triple negative breast cancer

Pang

Virani

Kidwell

et al. 2014

Journal of Cell Communication and Signaling

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Invasive breast carcinomas are heterogeneous and exhibit distinct molecular features and biological behavior. Understanding the underlying molecular events that promote breast cancer progression is necessary to improve treatment and prognostication. TGF-β receptor III (TBR3) is a member of the TGF-β signaling pathway, with functions in cell proliferation and migration in malignancies, including breast cancer. Recent studies propose that TBR3 may function as a tumor suppressor and that its loss may correlate with disease progression. However, there are limited data on the expression of TBR3 in breast cancer in relationship to tumor type, hormonal receptor status and HER-2/neu, and patient outcome. In this study, we investigated the expression of TBR3 in a cohort of 205 primary invasive breast carcinomas in tissue microarrays (TMAs), with comprehensive clinical, pathological and follow-up information. Sections were stained for TBR3 and evaluated for intensity of reactivity based on a 4-tiered scoring system (1 to 4; TBR3 low=scores 1-2; TBR3 high=scores 3-4). Of the 205 invasive carcinomas, 123 were luminal type (95 type A, 28 type B), 8 were HER-2 type, and 62 were triple negative (TN). TBR3 was high in 112 (55 %) and low in 93 (45 %) cases. Low TBR3 was associated with higher histological grade and worse disease free and overall survival, all features of biologically aggressive breast carcinomas. TBR3 was significantly associated with the subtype of breast cancer, as low TBR3 was detected in 95 % of TN compared to 22 % of luminal tumors ( p<0.0001). We discovered a significant association between low TBR3 protein expression, TN breast cancer phenotype, and disease progression. These data suggest that TBR3 loss might be linked to the development of TN breast cancers and pave the way to investigating whether restoring TBR3 function may be a therapeutic strategy against TN breast carcinomas.

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The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

Cited by 128 publications

References 38 publications

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

Characterization of type III TGF‐β receptor expression in invasive breast carcinomas: a potential new marker and target for triple negative breast cancer

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