Opposing roles and potential antagonistic mechanism between TGF-β and BMP pathways: Implications for cancer progression

Ning, Junya; Zhao, Yi; Ye, Yingnan; Yu, Jinpu

doi:10.1016/j.ebiom.2019.02.033

Cited by 69 publications

(63 citation statements)

References 139 publications

(146 reference statements)

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“…BMP activity in both regions was reduced (relative to myosin expression) ~50% in gnptab –/– morphants ( Figure 3F and Supplemental Figure 2 ). Due to significant crosstalk between the TGF-β and BMP signaling systems, high TGF-β activity has been shown to negatively impact BMP activity ( 46 , 47 ). To address this possibility, gnptab –/– morphants were treated at 52 hpf with the TGFBRI inhibitor SB505124 (10 μM).…”

Section: Resultsmentioning

confidence: 99%

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Lu¹,

Moreland²,

Christian³

et al. 2020

JCI Insight

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Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease. Aberrant localization and expression of cathepsin proteases can perpetuate later-stage heart diseases, but their contribution toward CHDs is unclear. To investigate the contribution of cathepsins during cardiovascular development and congenital disease, we analyzed the pathogenesis of cardiac defects in zebrafish models of the lysosomal storage disorder mucolipidosis II (MLII). MLII is caused by mutations in the GlcNAc-1-phosphotransferase enzyme (Gnptab) that disrupt carbohydrate-dependent sorting of lysosomal enzymes. Without Gnptab, lysosomal hydrolases, including cathepsin proteases, are inappropriately secreted. Analyses of heart development in gnptab -deficient zebrafish show cathepsin K secretion increases its activity, disrupts TGF-β–related signaling, and alters myocardial and valvular formation. Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. Collectively, these data identify mislocalized cathepsin K as an initiator of cardiac disease in this lysosomal disorder and establish cathepsin inhibition as a viable therapeutic strategy.

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Section: Resultsmentioning

confidence: 99%

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Lu¹,

Moreland²,

Christian³

et al. 2020

JCI Insight

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“…SKIL encodes the Ski-related novel protein N (SnoN) which is associated with the TGF β /SMAD pathway and, as the studies show, also with the pathway dependent on the p53 gene, which plays a key role in carcinogenesis [ 52 , 53 ]. Cao et al showed a strong correlation between the expression of SKIL and TGF β 1 of hepatocellular carcinoma; the level of expression of which was significantly elevated compared to controls [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

The Influence of Adalimumab and Cyclosporine A on the Expression Profile of the Genes Related to TGFβ Signaling Pathways in Keratinocyte Cells Treated with Lipopolysaccharide A

Adwent

Grabarek

Kojs‐Mrożkiewicz³

et al. 2020

Mediators of Inflammation

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Background. In the treatment of moderate to severe psoriasis, cyclosporine A (CsA) conventional therapy is used and biological, anti-cytokine treatment using, for example, anti-TNF drug—adalimumab. Aim. This study aimed at investigating the effect of CsA and adalimumab on the profile of mRNAs and protein expression associated with transforming growth factor β (TGFβ) pathways in human keratinocyte (HaCaT) culture previously exposed to lipopolysaccharide (LPS). Materials and Methods. HaCaT culture was exposed to 1 ng/ml LPS for 8 hours+8 μg/ml adalimumab for 2, 8, and 24 hours or 1 ng/ml LPS for 8 hours+100 ng/ml CsA for 2, 8, and 24 hours and compared to the control culture. Sulphorodamine B cytotoxicity assay was performed. The expression profile of mRNA related to TGFβ paths was indicated by microarray and RTqPCR analyses. The ELISA test was used to analyze changes on the proteome level. Statistical analysis consisted of ANOVA analysis and the post hoc Tukey test (p<0.05). Results. The cytotoxicity test showed that LPS, adalimumab, and cyclosporine in the concentration used in this experiment did not have any cytotoxicity effect on HaCaT cells. The largest fold changes (FC) in expression in (∣FC∣>4.00) was determined for TGFβ1-3, TGFβRI-III, SKIL, SMURF2, SMAD3, BMP2, BMP6, JAK2, UBE2D1, SKP2, EDN1, and PRKAR2B (p<0.05). In addition, on the protein level, the direct changes observed at mRNA were the same. Conclusion. Analysis of the microarray expression profile of genes associated with TGFβ signaling pathways has demonstrated the potential of cyclosporin A and adalimumab to induce changes in their transcriptional activity. The anti-TNF drug seems to affect TGFβ cascades to a greater extent than cyclosporin A. The obtained results suggest that the regularity of taking the drug is important for the efficacy of psoriasis therapy.

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“…Conversely, BMPs binding to BMPRI/I can block the activation of TGFβ receptors via upregulating CTGF itself and SMAD6. Moreover, one pathway can overcome the other when competing for the use of SMAD4 [148]. The type I membrane glycoprotein endoglin was found to act as a modulator of the relative impact of the TGFβ and BMP axes on malignancy in Ewing sarcoma and melanoma cells.…”

Section: Crosstalk Between Bmp and Tgfβ Pathway In Cancermentioning

confidence: 99%

The Interactivity between TGFβ and BMP Signaling in Organogenesis, Fibrosis, and Cancer

Dituri

Cossu

Mancarella

et al. 2019

Cells

100

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The Transforming Growth Factor beta (TGFβ) and Bone Morphogenic Protein (BMP) pathways intersect at multiple signaling hubs and cooperatively or counteractively participate to bring about cellular processes which are critical not only for tissue morphogenesis and organogenesis during development, but also for adult tissue homeostasis. The proper functioning of the TGFβ/BMP pathway depends on its communication with other signaling pathways and any deregulation leads to developmental defects or diseases, including fibrosis and cancer. In this review we explore the cellular and physio-pathological contexts in which the synergism or antagonism between the TGFβ and BMP pathways are crucial determinants for the normal developmental processes, as well as the progression of fibrosis and malignancies.

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Opposing roles and potential antagonistic mechanism between TGF-β and BMP pathways: Implications for cancer progression

Cited by 69 publications

References 139 publications

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

The Influence of Adalimumab and Cyclosporine A on the Expression Profile of the Genes Related to TGFβ Signaling Pathways in Keratinocyte Cells Treated with Lipopolysaccharide A

The Interactivity between TGFβ and BMP Signaling in Organogenesis, Fibrosis, and Cancer

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