Role of vasostatin-1 C-terminal region in fibroblast cell adhesion

Dondossola, Eleonora; Gasparri, Anna Maria; Bachi, Ángela; Longhi, Renato; Metz-Boutigue, Marie Hélène; Tota, Bruno; Helle, Karen B.; Curnis, Flavio; Corti, Angelo

doi:10.1007/s00018-010-0319-5

Cited by 17 publications

(14 citation statements)

References 60 publications

(70 reference statements)

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“…9 Experimental evidence suggests that CgA1-78 can interact with heparan sulfate proteoglycans on endothelial cells and increase caveolae-dependent endocytosis. 36 CgA1-78 can also interact with membrane phospholipids, particularly with phosphatidylserine, an anionic phospholipid exposed on the surface of tumor endothelial cells, 10,[37][38][39] and inhibit VEGF-induced phosphorylation of ERK, an enzyme crucial for the induction of a cascade of events leading to increased cell proliferation and migration in angiogenesis. 40,41 In addition, CgA1-78 can inhibit TNF-induced phosphorylation of p38-MAPK by a pertussis toxin sensitive mechanism, a pathway important for the disassembly of adherence junctions in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

A new chromogranin A–dependent angiogenic switch activated by thrombin

Crippa

Bianco

Colombo

et al. 2013

Blood

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151

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• Circulating chromogranin A and its fragments form a balance of anti-and proangiogenic factors regulated by thrombin-dependent cleavage.• The alteration of this balance could provide a new mechanism for triggering angiogenesis in cancer and other pathophysiologic conditions.Angiogenesis, the formation of blood vessels from pre-existing vasculature, is regulated by a complex interplay of anti and proangiogenic factors. We found that physiologic levels of circulating chromogranin A (CgA), a protein secreted by the neuroendocrine system, can inhibit angiogenesis in various in vitro and in vivo experimental models. Structure-activity studies showed that a functional antiangiogenic site is located in the C-terminal region, whereas a latent anti-angiogenic site, activated by cleavage of Q76-K77 bond, is present in the N-terminal domain. Cleavage of CgA by thrombin abrogated its anti-angiogenic activity and generated fragments (lacking the C-terminal region) endowed of potent proangiogenic activity. Hematologic studies showed that biologically relevant levels of forms of full-length CgA and CgA1-76 (anti-angiogenic) and lower levels of fragments lacking the C-terminal region (proangiogenic) are present in circulation in healthy subjects. Blood coagulation caused, in a thrombin-dependent manner, almost complete conversion of CgA into fragments lacking the C-terminal region. These results suggest that the CgA-related circulating polypeptides form a balance of anti and proangiogenic factors tightlyregulated byproteolysis. Thrombin-induced alteration of this balance could provide a novel mechanism for triggering angiogenesis in pathophysiologic conditions characterized by prothrombin activation. (Blood. 2013;121(2):392-402) IntroductionAngiogenesis, the process of formation of new blood vessels from pre-existing vessels, is tightly regulated by the coordinated action of anti and proangiogenic factors. [1][2][3] When this balance is disturbed, the result is either excessive or insufficient angiogenesis. Altered angiogenesis, causing excessive or insufficient blood vessel growth, is a common denominator underlying many pathologic conditions, including cardiovascular diseases, macular degeneration, skin diseases, diabetic ulcers, stroke, rheumatoid arthritis, cancer, and many others. [1][2][3] A growing body of evidence suggests that angiogenesis can be regulated by peptides derived from proteins released by neurons and neuroendocrine cells. For example, we have previously shown the recombinant fragment 1-78 of human chromogranin A (CgA), a 439-residue long protein stored in the secretory granules of many endocrine cells, neurons, and cardiomyocytes 4-6 can inhibit angiogenesis in experimental models. 7 Other investigators have shown that a synthetic fragment encompassing residues 352-372 (CgA352-372) can promote angiogenesis. 8 Studies on the mechanism of action have shown that CgA1-78 (also called vasostatin-1) can inhibit endothelial cell proliferation, migration, and invasion induced by vascular endothelial growth factor...

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Section: Discussionmentioning

confidence: 99%

A new chromogranin A–dependent angiogenic switch activated by thrombin

Crippa

Bianco

Colombo

et al. 2013

Blood

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151

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“…Evidence was obtained to suggest that adhesion requires activation of specific cellular mechanisms (including actin polymerization) and that it is not purely related to mechanical or sticky effects (Dondossola et al 2010). The results of binding studies performed with fibroblasts and with a series of VS-1-deletion mutants support a model of interaction based on binding to cell membrane via C-terminal domain (residues 47-78).…”

Section: Cga and Fibroblastsmentioning

confidence: 97%

Chromogranin A and the Tumor Microenvironment

Corti

2010

Cell Mol Neurobiol

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Chromogranin A (CgA) is an acidic glycoprotein belonging to a family of regulated secretory proteins stored in the dense core granules of the adrenal medulla and of many other neuroendocrine cells and neurons. This protein is frequently used as a diagnostic and prognostic serum marker for a range of neuroendocrine tumors. Circulating CgA is also increased in patients with other diseases, including subpopulations of patients with non-neuroendocrine tumors, with important prognostic implications. A growing body of evidence suggests that CgA is more than a diagnostic/prognostic marker for cancer patients. Indeed, results of in vitro experiments and in vivo studies in animal models suggest that this protein and its fragments can affect several elements of the tumor microenvironment, including fibroblasts and endothelial cells. In this article, recent findings implicating CgA as a modulator of the tumor microenvironment and suggesting that abnormal secretion of CgA could play important roles in tumor progression and response to therapy in cancer patients are reviewed and discussed.

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“…b Schematic representation of the N-terminal domain of CgA showing the RGD motif and the amphipathic a-helix. Antibody epitope topography and ezrin-binding-protein-50-homology domain [15][16][17][18] are also indicated. mAb 7D1 and 5A8, but not B4E11 can block the CgA/avb6 interaction (RGE) on skin wound healing in mice.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that CgA can also inhibit the adhesion of fibroblasts to various extracellular-matrix proteins, whereas the CgA 1-78 fragment (VS-1) can promote cell adhesion and spreading [15][16][17][18]. CgA and VS-1 can also enhance endothelial cell-cell adhesion and protect the endothelial barrier integrity from vascular leakage induced by tumor necrosis factor alpha [19,20].…”

Section: Introductionmentioning

confidence: 99%

Chromogranin A binds to αvβ6-integrin and promotes wound healing in mice

Curnis

Gasparri

Longhi

et al. 2012

Cell. Mol. Life Sci.

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Chromogranin A (CgA), a secretory protein expressed by many neuroendocrine cells, neurons, cardiomyocytes, and keratinocytes, is the precursor of various peptides that regulate the carbohydrate/lipid metabolism and the cardiovascular system. We have found that CgA, locally administered to injured mice, can accelerate keratinocyte proliferation and wound healing. This biological activity was abolished by the Asp(45)Glu mutation. CgA and its N-terminal fragments, but not the corresponding Asp(45)Glu mutants, could selectively recognize the αvβ6-integrin on keratinocytes (a cell-adhesion receptor that is up-regulated during wound healing) and regulate keratinocyte adhesion, proliferation, and migration. No binding was observed to other integrins such as αvβ3, αvβ5, αvβ8, α5β1, α1β1, α3β1, α6β4, α6β7 and α9β1. Structure-activity studies showed that the entire CgA(39-63) region is crucial for αvβ6 recognition (K(i) = 7 nM). This region contains an RGD site (residues CgA(43-45)) followed by an amphipathic α-helix (residues CgA(47-63)), both crucial for binding affinity and selectivity. These results suggest that the interaction of the RGD/α-helix motif of CgA with αvβ6 regulates keratinocyte physiology in wound healing.

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Role of vasostatin-1 C-terminal region in fibroblast cell adhesion

Cited by 17 publications

References 60 publications

A new chromogranin A–dependent angiogenic switch activated by thrombin

A new chromogranin A–dependent angiogenic switch activated by thrombin

Chromogranin A and the Tumor Microenvironment

Chromogranin A binds to αvβ6-integrin and promotes wound healing in mice

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