Crystal Structure of the LG3 Domain of Endorepellin, an Angiogenesis Inhibitor

Le, Binh; Kim, Hun; Choi, Joon‐Hwan; Kim, Jin-Hahn; Hahn, Myong‐Joon; Lee, Cheolju; Kim, Kyeong Kyu; Hwang, Hye‐Yeon

doi:10.1016/j.jmb.2011.09.048

Cited by 18 publications

(21 citation statements)

References 37 publications

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“…Recently, the crystal structure of LG3 as well as the binding site for the α2β1 integrin has been unveiled [207]. Based on a jellyroll fold, LG3 is constituted of 200 amino acids with an architecture formed by a β-sandwich composed of 15 anti-parallel β-strands.…”

Section: Perlecan a Large Multimodular Heparan Sulfate Proteoglycanmentioning

confidence: 99%

“…Other element belonging to the EF loop could be also involved in the angiostatic activity of LG3. Moreover, Ca 2+ is needed for this function but it is not required for the binding to the α2β1 integrin [207]. We previously proposed that the DAPGQYG sequence, located at the N-terminus of LG3, could be involved in the processing of endorepellin by Asp-N endoproteinases [189].…”

Section: Perlecan a Large Multimodular Heparan Sulfate Proteoglycanmentioning

confidence: 99%

“…Subsequently, it was confirmed as the main cleavage site mediated by BMP-1/Tolloid-like metalloproteases [193]. New surface plasmon resonance analyses have identified this site, in particular the Asp4197, as a key residue involved in the anti-migratory effects exerted by endorepellin [207]. …”

Section: Perlecan a Large Multimodular Heparan Sulfate Proteoglycanmentioning

confidence: 99%

See 2 more Smart Citations

Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers

Poluzzi

Iozzo

Schaefer

2016

Advanced Drug Delivery Reviews

111

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Traditional cancer therapy typically targets the tumor proper. However, newly-formed vasculature exerts a major role in cancer development and progression. Autophagy, as a biological mechanism for clearing damaged proteins and oxidative stress products released in the tumor milieu, could help in tumor resolution by rescuing cells undergoing modifications or inducing autophagic-cell death of tumor blood vessels. Cleaved fragments of extracellular matrix proteoglycans are emerging as key players in the modulation of angiogenesis and endothelial cell autophagy. An essential characteristic of cancer progression is the remodeling of the basement membrane and the release of processed forms of its constituents. Endostatin, generated from collagen XVIII, and endorepellin, the C-terminal segment of the large proteoglycan perlecan, possess a dual activity as modifiers of both angiogenesis and endothelial cell autophagy. Manipulation of these endogenously-processed forms, located in the basement membrane within tumors, could represent new therapeutic approaches for cancer eradication.

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Section: Perlecan a Large Multimodular Heparan Sulfate Proteoglycanmentioning

confidence: 99%

Section: Perlecan a Large Multimodular Heparan Sulfate Proteoglycanmentioning

confidence: 99%

See 1 more Smart Citation

Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers

Poluzzi

Iozzo

Schaefer

2016

Advanced Drug Delivery Reviews

111

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“…Endorepellin is an 85-kDa glycoprotein consisting of three laminin-like globular (LG) repeats separated by epidermal growth factor (EGF)-like module doublets. The crystal structure of the LG3 domain has been recently solved (103). This region is made up of about 200 amino acids and is constructed as a 15-stranded anti-parallel β sandwich forming a jellyroll fold, characteristic of LG domains (Figure 1B).…”

Section: Endorepellin the C-terminal Angiostatic Fragment Of Perlecanmentioning

confidence: 99%

“…This region is made up of about 200 amino acids and is constructed as a 15-stranded anti-parallel β sandwich forming a jellyroll fold, characteristic of LG domains (Figure 1B). Notably, Asp 4197 located near the N-terminus of LG3, might be a potential binding site for the α2β1 integrin, as mutation of this residue LG3 activity (103). …”

Section: Endorepellin the C-terminal Angiostatic Fragment Of Perlecanmentioning

confidence: 99%

The role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy

Douglass¹,

Goyal²,

Iozzo³

2015

Connective Tissue Research

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During tumor growth and angiogenesis there is a dynamic remodelling of tissue architecture often accompanied by the release of extracellular matrix constituents full of biological activity. One of the key constituents of the tumor microenvironment is the large heparan sulfate proteoglycan perlecan. This proteoglycan, strategically located at cell surfaces and within basement membranes, is a well-defined pro-angiogenic molecule when intact. However, when partially processed by proteases released during cancer remodelling and invasion, the C-terminal fragment of perlecan, known as endorepellin, has opposite effects than its parent molecule. Endorepellin is a potent inhibitor of angiogenesis by exerting a dual receptor antagonism by simultaneously engaging VEGFR2 and α2β1 integrin. Signaling through the α2β1 integrin leads to actin disassembly and block of endothelial cell migration, necessary for capillary morphogenesis. Signaling through the VEGFR2 induces dephosphorylation of the receptor via activation of SHP-1 and suppression of downstream proangiogenic effectors, especially attenuating VEGFA expression. A novel and emerging role of endorepellin is its ability to evoke autophagy by activating Peg3 and various canonical autophagic markers. This effect is specific for endothelial cells as these are the primary cells expressing both VEGFR2 and α2β1 integrin. Thus, an endogenous fragment of a ubiquitous proteoglycan can regulate both angiogenesis and autophagy through a dual receptor antagonism. The biological properties of this natural endogenous protein place endorepellin as a potential therapeutic agent against cancer or diseases where angiogenesis is prominent.

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Proteoglycans of basement membranes: Crucial controllers of angiogenesis, neurogenesis, and autophagy

Mongiat,

Pascal,

Poletto

et al. 2024

Proteoglycan Research

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Antiangiogenic therapy is an established method for the treatment of several cancers and vascular‐related diseases. Most of the agents employed target the vascular endothelial growth factor A, the major cytokine stimulating angiogenesis. However, the efficacy of these treatments is limited by the onset of drug resistance. Therefore, it is of fundamental importance to better understand the mechanisms that regulate angiogenesis and the microenvironmental cues that play significant role and influence patient treatment and outcome. In this context, here we review the importance of the three basement membrane (BM) heparan sulfate proteoglycans (HSPGs), namely perlecan, agrin, and collagen XVIII. These HSPGs are abundantly expressed in the vasculature and, due to their complex molecular architecture, they interact with multiple endothelial cell receptors, deeply affecting their function. Under normal conditions, these proteoglycans exert proangiogenic functions. However, in pathological conditions such as cancer and inflammation, extracellular matrix remodeling leads to the degradation of these large precursor molecules and the liberation of bioactive processed fragments displaying potent angiostatic activity. These unexpected functions have been demonstrated for the C‐terminal fragments of perlecan and collagen XVIII, endorepellin, and endostatin. These bioactive fragments can also induce autophagy in vascular endothelial cells which contributes to angiostasis. Overall, BM proteoglycans deeply affect angiogenesis counterbalancing proangiogenic signals during tumor progression and represent possible means to develop new prognostic biomarkers and novel therapeutic approaches for the treatment of solid tumors.

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Crystal Structure of the LG3 Domain of Endorepellin, an Angiogenesis Inhibitor

Cited by 18 publications

References 37 publications

Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers

Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers

The role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy

Proteoglycans of basement membranes: Crucial controllers of angiogenesis, neurogenesis, and autophagy

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