Perlecan a multifunctional extracellular proteoglycan scaffold

Farach-Carson, Mary C.; Carson, Daniel D.

doi:10.1093/glycob/cwm043

Cited by 132 publications

(120 citation statements)

References 88 publications

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“…Human recombinant endorepellin and LG3 harboring a His 6 tag at their C termini were purified on a nickel-nitrilotriacetic acid resin column as previously described (7). The soluble ectodomain heterodimer of the ␣2␤1 integrin was generated as previously described (21).…”

Section: Methodsmentioning

confidence: 99%

“…Accordingly, much attention has been invested in the search for and characterization of anti-angiogenic agents to enable regulated and inhibited tumor angiogenesis as part of cancer therapies (1). The proteoglycan perlecan plays a key role in the angiogenic process, primarily by modulating the availability and activity of growth factors involved in angiogenesis such as fibroblast growth factor 2, VEGF, 3 and platelet-derived growth factor (2)(3)(4)(5)(6). The most C-terminal part of perlecan (domain V), named endorepellin, is a powerful angiogenic inhibitor (7).…”

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confidence: 99%

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Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Woodall

Nyström

Iozzo

et al. 2008

Journal of Biological Chemistry

102

106

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Endorepellin, the C-terminal module of perlecan, has angiostatic activity. Here we provide definitive genetic and biochemical evidence that the functional endorepellin receptor is the ␣2␤1 integrin. Notably, the specific endorepellin binding to the receptor was cation-independent and was mediated by the ␣2 I domain. We show that the anti-angiogenic effects of endorepellin cannot occur in the absence of ␣2␤1. Microvascular endothelial cells from ␣2␤1 ؊/؊ mice, but not those isolated from either wild-type or ␣1␤1 ؊/؊ mice, did not respond to endorepellin. Moreover, syngeneic Lewis lung carcinoma xenografts in ␣2␤1 ؊/؊ mice failed to respond to systemic delivery of endorepellin. In contrast, endorepellin inhibited tumor growth and angiogenesis in the wild-type mice expressing integrin ␣2␤1. We conclude that the angiostatic effects of endorepellin in vivo are mediated by a specific interaction of endorepellin with the ␣2␤1 integrin receptor.The incorporation of new blood vessels into growing neoplasms is a prerequisite for tumor viability and progression. Accordingly, much attention has been invested in the search for and characterization of anti-angiogenic agents to enable regulated and inhibited tumor angiogenesis as part of cancer therapies (1). The proteoglycan perlecan plays a key role in the angiogenic process, primarily by modulating the availability and activity of growth factors involved in angiogenesis such as fibroblast growth factor 2, VEGF, 3 and platelet-derived growth factor (2-6). The most C-terminal part of perlecan (domain V), named endorepellin, is a powerful angiogenic inhibitor (7). Endorepellin carries three laminin-like globular (LG) domains separated by epidermal growth factor-like repeats (8) and binds to numerous extracellular matrix proteins, growth factors, and receptors including collagen XVIII, fibulin-2, nidogen, fibroblast growth factor 7, fibroblast growth factor-binding protein, ECM1 (7, 9 -12), ␣-dystroglycan, and integrin ␣2␤1 (9, 13-16). The endorepellin anti-angiogenic effect is parallel to several proteolytically released fragments from vascular basement membrane such as endostatin, the NC-1 domain of collagen type XVIII, and tumstatin, the NC-1 domain the of type IV collagen ␣3 chain (8,17,18). These fragments principally act on endothelial cells as "negative" ligands for specific integrin receptors. Endorepellin is a potent inhibitor in several angiogenesis assays such as endothelial cell migration, collagen-induced capillary morphogenesis, blood vessel recruitment into Matrigel plugs, and chicken chorioallontoic membrane (7,19). It also effectively retards in vivo tumor growth by specifically targeting tumor angiogenesis (20). We hypothesize that endorepellin takes effect via the LG3 domain binding to the integrin ␣2␤1 causing actin disassembly and therefore affecting three key steps of angiogenesis: endothelial cell adhesion, migration, and morphogenesis.Here we have further investigated the endorepellin-␣2␤1 integrin interactions by using cell-free experiments with a solub...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Woodall

Nyström

Iozzo

et al. 2008

Journal of Biological Chemistry

102

106

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“…Physiologically, perlecan plays a prominent role in regulating cellular proliferation, differentiation, organization, and mediating inflammation [106]. Perlecan derives its functionality from five protein subdomains which share their sequence homology with several other proteins [107]. Domain 1 contains an SEA (Sperm protein, Enteokinase, Agrin) module and three SGD (Ser-Gly-Asp) tripeptide sequences to which three heparan sulfate (HS) glycosaminoglycans attach.…”

Section: The Basement Membrane Supports Valve Endothelial Cells and Amentioning

confidence: 99%

Extracellular Matrix Organization, Structure, and Function

Wiltz¹,

Arevalos²,

Balaoing³

et al. 2013

Calcific Aortic Valve Disease

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“…HSPGs are defined as proteins containing one or more covalently attached heparan sulfate chains supporting its function as a natural anticoagulant. HSPGs can be divided into three major classes: (1) lipid-anchored, e.g., the glypicans; (2) transmembrane, e.g., syndecans; and (3) extracellular or secreted, a group that includes perlecan [42]. HSPGs had been found in cartilage [43], bone stroma [44], uterine decidua [45], and follicular fluid [46].…”

Section: Discussionmentioning

confidence: 99%

What maintains the high intra-follicular estradiol concentration in pre-ovulatory follicles?

Bentov

Jurisicova

Kenigsberg

et al. 2015

J Assist Reprod Genet

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Purpose The purpose of the study was to establish the mechanism by which the estrogen concentration difference between the follicular fluid and the serum is maintained. Methods We used dialysis membrane with a pore size of <3 KD to characterize the estrogen-binding capacity of the follicular fluid. We performed PCR, western blot, and ELISA on luteinized granulosa cells to determine if sex hormonebinding globulin (SHBG) is produced by granulosa cells, and finally we used affinity columns and mass spectrometry to identify the estrogen-binding protein in the follicular fluid. Results We found that a significant estrogen concentration difference is maintained in a cell-free system and is lost with proteolysis of the follicular fluid proteins. Luteinized granulosa cells are likely not a source of SHBG, as we were not able to detect expression of SHBG in these cells. Perlecan was the most highly enriched follicular fluid protein in the affinity columns. Conclusions We were able to identify perlecan as the most likely candidate for the major estrogen-binding protein in the follicular fluid.

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Perlecan a multifunctional extracellular proteoglycan scaffold

Cited by 132 publications

References 88 publications

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Extracellular Matrix Organization, Structure, and Function

What maintains the high intra-follicular estradiol concentration in pre-ovulatory follicles?

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