Unique functions for Notch4 in murine embryonic lymphangiogenesis

Muley, Ajit; Uh, Minji K.; Simone, Glicella Salazar-De; Swaminathan, Bhairavi; James, Jennifer M.; Murtomäki, Aino; Youn, Seock Won; McCarron, Joseph D; Kitajewski, Chris; Buethe, Maria Gnarra; Riitano, Gloria; Mukouyama, Yoh-suke; Kitajewski, Jan; Shawber, Carrie J.

doi:10.1007/s10456-021-09822-5

Cited by 15 publications

(18 citation statements)

References 53 publications

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“…These genetic studies suggest that Notch4 may play a redundant role in developmental angiogenesis but also that Notch4 is moderately pro-angiogenic, consistent with what we observed with the treatment of N4 10-14 Fc peptibodies. Conversely, some studies suggest that Notch4 plays a specific role in specific endothelial pathologies, suggesting that treatment with N4 10-14 Fc peptibodies may show stronger effects under pathological conditions [32,[42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties

et al. 2022

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The Notch signaling pathway is an important therapeutic target for the treatment of inflammatory diseases and cancer. We previously created ligand-specific inhibitors of Notch signaling comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain, called Notch decoys, which bound ligands, blocked Notch signaling, and showed anti-tumor activity with low toxicity. However, the study of their function depended on virally mediated expression, which precluded dosage control and limited clinical applicability. We have refined the decoy design to create peptibody-based Notch inhibitors comprising the core binding domains, EGF-like repeats 10–14, of either Notch1 or Notch4. These Notch peptibodies showed high secretion properties and production yields that were improved by nearly 100-fold compared to previous Notch decoys. Using surface plasmon resonance spectroscopy coupled with co-immunoprecipitation assays, we observed that Notch1 and Notch4 peptibodies demonstrate strong but distinct binding properties to Notch ligands DLL4 and JAG1. Both Notch1 and Notch4 peptibodies interfere with Notch signaling in endothelial cells and reduce expression of canonical Notch targets after treatment. While prior DLL4 inhibitors cause hyper-sprouting, the Notch1 peptibody reduced angiogenesis in a 3-dimensional in vitro sprouting assay. Administration of Notch1 peptibodies to neonate mice resulted in reduced radial outgrowth of retinal vasculature, confirming anti-angiogenic properties. We conclude that purified Notch peptibodies comprising EGF-like repeats 10–14 bind to both DLL4 and JAG1 ligands and exhibit anti-angiogenic properties. Based on their secretion profile, unique Notch inhibitory activities, and anti-angiogenic properties, Notch peptibodies present new opportunities for therapeutic Notch inhibition.

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Section: Discussionmentioning

confidence: 99%

Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties

et al. 2022

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“…The primary antibodies used for IF were Notch4 (1:100, Notch4-ICD, kindly provided by Dr. Carrie J. Shawber; ref. 29 ), Amylase (1:100, catalog no. : sc-46657, Santa Cruz Biotechnology), CK19 (1:25, TROMA3; DSHB).…”

Section: Methodsmentioning

confidence: 99%

Inactivation ofNotch4Attenuated Pancreatic Tumorigenesis in Mice

Saeki

Qiu

Friedman

et al. 2022

Cancer Research Communications

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Expression of the Notch family of receptors are often upregulated in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on Notch4, which had not been investigated in PDAC. We generated KC (LSL-KrasG12D;p48-Cre), N4-/-KC (Notch4-/-;LSL-KrasG12D;p48-Cre), PKC (p16fl/fl;LSL-KrasG12D;p48-Cre), and N4-/-PKC (Notch4 -/-; p16fl/f l;LSL-KrasG12D;p48-Cre) genetically engineered mouse models (GEMMs). We performed caerulein treatment in both KC and N4-/-KC mice, and the development of acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions were significantly diminished in the N4-/-KC than in the KC GEMM (p=0.01). This in vivo result was validated by in vitro ADM induction of the explant cultures of pancreatic acinar cells from the N4-/-KC and KC mice (p<0.001), confirming that Notch4 is an important contributor to early pancreatic tumorigenesis. To evaluate the role of Notch4 in the later stage of pancreatic tumorigenesis, we compared the PKC and N4-/-PKC mice. The N4-/-PKC mice had better overall survival (p=0.012) and significantly reduced tumor burden (PanIN: p=0.018 at 2 months, PDAC: p=0.039 at 5 months) compared to the PKC GEMM. RNA-Seq analysis of pancreatic tumor cell lines derived from the PKC and N4-/-PKC GEMMs revealed 408 genes were differentially expressed (FDR<0.05) and Pcsk5 as a potential downstream effector of the Notch4 signaling pathway (p<0.001). Low expression of Pcsk5 positively correlates with good survival in PDAC patients (p=0.028). We have identified a novel role for Notch4 signaling with tumor promoting function in pancreatic tumorigenesis. Our study also uncovered a novel association between Pcsk5 and Notch4 signaling in PDAC.

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“…Additionally, TMEM100-deficiency led to an impairment in the formation of endothelial and smooth muscle cell layers in the lung in Tmem100-knockout lungs [ 19 ]. Moreover, TMEM100 regulates NOTCH, a negative regulator of the specification of lymphatic endothelial cells [ 20 , 40 ]. In Tmem100-deficient embryos, there was a suppression of NOTCH signaling in arterial ECs and the endocardium and impairments in lymphedema and enlarged lymphatic vessels [ 20 ].…”

Section: Molecular Signaling Affected By Tmem100mentioning

confidence: 99%

The Role of a Lung Vascular Endothelium Enriched Gene TMEM100

2023

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Transmembrane protein 100 (TMEM100) is a crucial factor in the development and maintenance of the vascular system. The protein is involved in several processes such as angiogenesis, vascular morphogenesis, and integrity. Furthermore, TMEM100 is a downstream target of the BMP9/10 and BMPR2/ALK1 signaling pathways, which are key regulators of vascular development. Our recent studies have shown that TMEM100 is a lung endothelium enriched gene and plays a significant role in lung vascular repair and regeneration. The importance of TMEM100 in endothelial cells’ regeneration was demonstrated when Tmem100 was specifically deleted in endothelial cells, causing an impairment in their regenerative ability. However, the role of TMEM100 in various conditions and diseases is still largely unknown, making it an interesting area of research. This review summarizes the current knowledge of TMEM100, including its expression pattern, function, molecular signaling, and clinical implications, which could be valuable in the development of novel therapies for the treatment of cardiovascular and pulmonary diseases.

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Unique functions for Notch4 in murine embryonic lymphangiogenesis

Cited by 15 publications

References 53 publications

Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties

Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties

Inactivation ofNotch4Attenuated Pancreatic Tumorigenesis in Mice

The Role of a Lung Vascular Endothelium Enriched Gene TMEM100

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