Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1

Saitô, Takako; Bokhove, Marcel; Croci, Romina; Zamora-Caballero, Sara; Han, Ling; Letarte, Michelle; Sanctis, Daniele de; Jovine, Luca

doi:10.1016/j.celrep.2017.05.011

Cited by 121 publications

(188 citation statements)

References 55 publications

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“…Notably, a recent report demonstrated the crystal structures of the endoglin ectodomain and its complex with BMP9 (16). According to this report, the BMP9-endoglin Figure 7.…”

Section: Discussionmentioning

confidence: 86%

BMP9 directly induces rapid GSK3‐β phosphorylation in a Wnt‐independent manner through class I PI3K‐Akt axis in osteoblasts

Eiraku¹,

Chiba²,

Nakamura³

et al. 2019

The FASEB Journal

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Bone morphogenetic protein (BMP)9 has been reported to be the most potent BMP to induce bone formation. However, the details of BMP9‐transduced intracellular signaling remain ambiguous. Here, we have investigated signal transduction mechanisms of BMP9 in comparison to BMP2, another potent inducer of bone formation, in osteoblasts. In a mouse osteoblast cell line, BMP9 induced higher mRNA levels of alkaline phosphatase (ALP) and runt‐related transcription factor 2 (Runx2) than BMP2 within 2 h. Unlike BMP2, BMP9 induced rapid phosphorylation of glycogen synthase kinase 3‐β (GSK3‐β) and protein kinase B (Akt) and increased the cellular protein content of β‐catenin. BMP9 moderately increased mRNA levels of several canonical Wingless‐related integration site to lower degrees than BMP2. Furthermore, BMP9‐induced GSK3‐β phosphorylation was not inhibited by pretreatment with actinomycin D, cycloheximide, or Brefeldin A, indicating it is independent of Wnt protein secretion. BMP9‐induced GSK3‐β phosphorylation was abrogated by Akt or class I PI3K‐specific inhibitors. Moreover, inactivation of GSK3‐β by LiCl did not further promote ALP and Runx2 mRNA induction by BMP9 as significantly as that by BMP2. Notably, BMP9‐induced GSK3‐β phosphorylation was inhibited by small interfering RNA against endoglin and GIPC PDZ domain‐containing family, member 1. Taken together, our present findings have indicated that BMP9 directly activates GSK3β‐β‐catenin signaling pathway through class I PI3K‐Akt Axis in osteoblasts, which may be essential for the potent osteoinductive activity of BMP9.—Eiraku, N., Chiba, N., Nakamura, T., Amir, M. S., Seong, C.‐H., Ohnishi, T., Kusuyama, J., Noguchi, K., Matsuguchi, T. BMP9 directly induces rapid GSK3‐β phosphorylation in a Wnt‐independent manner through class I PI3K‐Akt axis in osteoblasts. FASEB J. 33, 12124‐12134 (2019). http://www.fasebj.org

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“…Notably, a recent report demonstrated the crystal structures of the endoglin ectodomain and its complex with BMP9 (16). According to this report, the BMP9-endoglin Figure 7.…”

Section: Discussionmentioning

confidence: 86%

BMP9 directly induces rapid GSK3‐β phosphorylation in a Wnt‐independent manner through class I PI3K‐Akt axis in osteoblasts

Eiraku¹,

Chiba²,

Nakamura³

et al. 2019

The FASEB Journal

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“…The juxtamembrane region of the endoglin ectodomain can be proteolytically targeted by the matrix metalloprotease 14 (MMP14; MT1-MMP) or by MMP-12 to release a soluble protein (either alone or in complex with exosomes), named sEng which encompasses most of its extracellular region [14][15][16][17][18][19]. Analysis of the three-dimensional structure of the endoglin ectodomain, has revealed the presence of an N-terminal orphan region (OR), and a C-terminal bipartite zona pellucida (ZP) module [20,21]. The OR of endoglin binds with high affinity to members of the TGF-β family, namely bone morphogenetic protein 9 (BMP9) and BMP10 [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

Gallardo-Vara

Gamella-Pozuelo

Pérez-Roque

et al. 2020

Cells

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Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators of hypertension, we analyzed the protein secretome of human endothelial cells in the presence of sEng. We found that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels, and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng + ) showed increased transcript levels of BMP4 in lungs, stomach, and duodenum, and increased circulating levels of BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng + mice, hypertension appeared 18 days after mating, coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 were positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng + mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the physiopathology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.

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“…BMP9, ALK1, endoglin, and Smad4 are members of the transforming growth factor-β signaling superfamily and all functionally interact in the same signal transduction axis (8). The cell surface receptor complex composed of the coreceptor endoglin, the endothelial BMP type I receptor ALK1, and a BMP type II receptor (e.g., BMPR2) is activated by sequential binding to the circulating ligands BMP9 and BMP10 (9)(10)(11). Mutations in BMPR2 cause familial pulmonary arterial hypertension (PAH), which can be observed in some HHT2 patients (12), further supporting the notion that ALK1 and BMPR2 functionally interact.…”

Section: Introductionmentioning

confidence: 81%

Sirolimus plus nintedanib treats vascular pathology in HHT mouse models

Ruíz

Zhao

Chandakkar

et al. 2019

Preprint

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Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1-ENG-Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K-Akt-mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine-kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs-including in HHT patient blood outgrowth ECs-and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in HHT patients. This study was supported by NIH/NHLBI grants R01HL139778 (to PM) and R01HL128525 (to SPO), DOD/CDMRP grant PR161205 (to SPO and PM), a Feinstein Institutes for Medical Research fund (to PM), Leducq foundation (ATTRACT, to SPO), and Barrow Neurological Foundation (to SPO). Conflict of interest:The Feinstein Institutes for Medical Research has filled a U.S. provisional patent application (#62/736,564) entitled "Combined sirolimus and nintedanib therapy for vascular lesions and hereditary hemorrhagic telangiectasia".

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Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1

Cited by 121 publications

References 55 publications

BMP9 directly induces rapid GSK3‐β phosphorylation in a Wnt‐independent manner through class I PI3K‐Akt axis in osteoblasts

BMP9 directly induces rapid GSK3‐β phosphorylation in a Wnt‐independent manner through class I PI3K‐Akt axis in osteoblasts

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

Sirolimus plus nintedanib treats vascular pathology in HHT mouse models

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