A role for the Tgf-<b>β</b>/Bmp co-receptor Endoglin in the molecular oscillator that regulates the hair follicle cycle

Calvo-Sánchez, María I.; Fernández-Martos, Sandra; Carrasco, Elisa; Moreno‐Bueno, Gema; Bernabéu, Carmelo; Quintanilla, Miguel; Espada, Jesús

doi:10.1093/jmcb/mjy051

Cited by 31 publications

(22 citation statements)

References 56 publications

(113 reference statements)

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“…Therefore, it is rare to identify the regulators that could mediate the downstream molecules simultaneously during feedback regulation of TGF-β and BMP signaling pathways in the same cell type and tissue or during the same biological process. A recent study has reported that endoglin, a newly identified common noncanonical receptor for TGF-β and BMP signaling pathways, could regulate the activities of both signaling pathways [ 11 ]. However, little is known regarding whether the core members within the pathways could feedback regulate their signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Feedback regulation is nowadays identified and defined as downstream signaling proteins that regulate the expression or activity of upstream signaling molecules directly or indirectly (via other regulators or signaling axis), which is also known as the main feedback model of TGF-β family signaling pathways [ 6 ]. The regulators involved in this feedback regulation progresses includes (i) miRNAs, such as SMAD4-miR-675-TGFBR1 [ 6 ], SMAD4-miR-425-TGFBR2 [ 7 ], SMAD4-miR-302-BMPR2 [ 8 ], and SMAD4-miR-24-3p-SMAD2 [ 9 ]; (ii) lncRNAs, such as SMAD2/3-lncRNA-MALAT1-TGFBR2 [ 10 ]; (iii) transcription factors (TFs), such as β-catenin (mediates SMAD4 induction of receptor) [ 11 ]; and (iv) transcriptional coregulators, such as Snail [ 12 ]. Additionally, the experimentally validated axes, including the SCF/STAT3 axis (mediates SMAD2 positive feedback regulation of TGF-β1) [ 13 ], SLIT2-Gremlin axis (mediates SMAD1/5/8/4 complex regulation of BMP2) [ 14 ], and so on.…”

Section: Introductionmentioning

confidence: 99%

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SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways

Liu

Yang

2021

IJMS

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TGF-β family signaling pathways, including TGF-β and BMP pathways, are widely involved in the regulation of health and diseases through downstream SMADs, which are also regulated by multiple validated mechanisms, such as genetic regulation, epigenetic regulation, and feedback regulation. However, it is still unclear whether R-SMADs or Co-SMAD can feedback regulate the TGF-β family signaling pathways in granulosa cells (GCs). In this study, we report a novel mechanism underlying the feedback regulation of TGF-β family signaling pathways, i.e., SMAD4, the only Co-SMAD, positive feedback activates the TGF-β family signaling pathways in GCs with a basal level of TGF-β ligands by interacting with the core promoters of its upstream receptors. Mechanistically, SMAD4 acts as a transcription factor, and feedback activates the transcription of its upstream receptors, including ACVR1B, BMPR2, and TGFBR2, of the canonical TGF-β signaling pathways by interacting with three coactivators (c-JUN, CREB1, and SP1), respectively. Notably, three different interaction modes between SMAD4 and coactivators were identified in SMAD4-mediated feedback regulation of upstream receptors through reciprocal ChIP assays. Our findings in the present study indicate for the first time that SMAD4 feedback activates the canonical TGF-β family signaling pathways in GCs, which improves and expands the regulatory mechanism, especially the feedback regulation modes of TGF-β family signaling pathways in ovarian GCs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways

Liu

Yang

2021

IJMS

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“…Recently, new roles for ENG have been described in physiological contexts. For instance, ENG is necessary to maintain correct hair follicle cycling and proper stimulation of hair follicle stem cell niches [ 115 ]. Furthermore, ENG mediates the regulation of the thermogenic gene program of beige adipocytes [ 116 ].…”

Section: The Physiological Role Of Endoglinmentioning

confidence: 99%

Endoglin in the Spotlight to Treat Cancer

Muñoz

Amaral

Puerto‐Camacho

et al. 2021

IJMS

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A spotlight has been shone on endoglin in recent years due to that fact of its potential to serve as both a reliable disease biomarker and a therapeutic target. Indeed, endoglin has now been assigned many roles in both physiological and pathological processes. From a molecular point of view, endoglin mainly acts as a co-receptor in the canonical TGFβ pathway, but also it may be shed and released from the membrane, giving rise to the soluble form, which also plays important roles in cell signaling. In cancer, in particular, endoglin may contribute to either an oncogenic or a non-oncogenic phenotype depending on the cell context. The fact that endoglin is expressed by neoplastic and non-neoplastic cells within the tumor microenvironment suggests new possibilities for targeted therapies. Here, we aimed to review and discuss the many roles played by endoglin in different tumor types, as well as the strong evidence provided by pre-clinical and clinical studies that supports the therapeutic targeting of endoglin as a novel clinical strategy.

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“…Moreover, it has been reported that WNT/β-catenin signaling during the onset of the anagen phase is accompanied by the specific expression of TGFβ2, that regulates proliferation, differentiation, and extracellular matrix production of dermal fibroblasts [19]. The interplay between WNT/β-catenin and TGFβ/BMP/SMAD to regulate stem cell niche function has been also described in different adult tissues, including the hair follicle [20]. It can be hypothesized that the GAG matrix produced by dermal fibroblasts in response to TGFβ/BMP/SMAD signaling is an essential component in the regulation of the hair follicle cycle and, particularly, in the feedback modulation of WNT/β-catenin signaling.…”

Section: Resultsmentioning

confidence: 99%

Sustained Human Hair Follicle Growth Ex Vivo in a Glycosaminoglycan Hydrogel Matrix

Fernández-Martos

Calvo-Sánchez

García-Alonso³

et al. 2019

IJMS

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Glycosaminoglycans (GAGs) and associated proteoglycans have important functions in homeostatic maintenance and regenerative processes (e.g., wound repair) of the skin. However, little is known about the role of these molecules in the regulation of the hair follicle cycle. Here we report that growing human hair follicles ex vivo in a defined GAG hydrogel mimicking the dermal matrix strongly promotes sustained cell survival and maintenance of a highly proliferative phenotype in the hair bulb and suprabulbar regions. This significant effect is associated with the activation of WNT/β-catenin signaling targets (CCDN1, AXIN2) and with the expression of stem cell markers (CK15, CD34) and growth factors implicated in the telogen/anagen transition (TGFβ2, FGF10). As a whole, these results point to the dermal GAG matrix as an important component in the regulation of the human hair follicle growth cycle, and to GAG-based hydrogels as potentially relevant modulators of this process both in vitro and in vivo.

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A role for the Tgf-β/Bmp co-receptor Endoglin in the molecular oscillator that regulates the hair follicle cycle

Cited by 31 publications

References 56 publications

SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways

SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways

Endoglin in the Spotlight to Treat Cancer

Sustained Human Hair Follicle Growth Ex Vivo in a Glycosaminoglycan Hydrogel Matrix

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