Disintegrins: A Family of Integrin Inhibitory Proteins from Viper Venoms

Gould, Robert J.; Polokoff, Mark A.; Friedman, Paul A.; Huang, Tur‐Fu; Holt, John Clifford; Cook, Jacquelynn J.; Niewiarowski, Stefan

doi:10.3181/00379727-195-43129b

Cited by 477 publications

(304 citation statements)

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“…There does not appear to be a relationship between chrysoptin and the disintegrins, a family of integrin inhibitory proteins from viper venoms (19). Both chrysoptin and the disintegrins are potent platelet inhibitors and inhibit fibrinogen binding.…”

Section: Discussionmentioning

confidence: 99%

Chrysoptin Is a Potent Glycoprotein IIb/IIIa Fibrinogen Receptor Antagonist Present in Salivary Gland Extracts of the Deerfly

Reddy

Kounga

Mariano

et al. 2000

Journal of Biological Chemistry

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Salivary gland lysates of the deerfly (genus Chrysops) contain chrysoptin, an inhibitor of ADP-induced platelet aggregation, which presumably assists the fly in obtaining a blood meal. Chrysoptin has now been isolated, and its cDNA has been cloned and expressed. Chrysoptin was purified to homogeneity using anion exchange and hydrophobic interaction chromatography and found to be a protein with a molecular mass of 65 kDa as determined by gel electrophoresis. N-terminal amino acid sequencing allowed for the synthesis of degenerate oligonucleotides that led to cloning, from salivary gland specific mRNA, of the cDNA encoding this platelet inhibitor. No RGD sites are present in the predicted sequence. A search of GenBank TM did not reveal significant sequence homology between chrysoptin and other proteins. The molecular mass predicted from the cDNA was 59 kDa. Predicted glycosylation and phosphorylation sites may account for this difference in molecular mass, as recombinant chrysoptin expressed in Sf21 cells had a molecular mass of 65 kDa, matching that of the natural protein. Chrysoptin functions by inhibiting the binding of fibrinogen to the fibrinogen/glycoprotein IIb/ IIIa receptor on platelets with an IC 50 of 95 pmol. These results reveal that insect salivary glands are a source of fibrinogen receptor antagonists.To facilitate blood feeding, hematophagous arthropods produce a number of bioactive substances that overcome the hemostatic mechanisms of the host. Arthropods trigger primary hemostasis by damaging blood vessels while probing the skin. As platelet aggregation is fundamental to hemostasis, some hematophagous arthropods appear to have evolved the ability to secrete platelet inhibitors in their saliva. Previous reports of antiplatelet activity in arthropod saliva include findings of prostacyclin activity in ticks (1, 2); apyrase activity in ticks (3), mosquitoes (4), blood-sucking bugs (5), and tse-tse flies (6); and a nitrosylheme protein from Rhodnius prolixus that has the capacity to release nitric oxide (7). Other than the protein from Rhodnius, these antiplatelet activities have not been well characterized, and it is not clear whether these or other activities account for the platelet inhibitory activity found in salivary gland lysates.Deerflies (genus Chrysops), also referred to as "greenheads" because of their brilliant green eyes, frequent the coast of the northeastern United States for several weeks in midsummer. Because these flies inflict painful bites that sometimes bleed, we reasoned that deerfly salivary gland extract (DFE) 1 might contain an inhibitor of platelet aggregation. We reported previously that DFE inhibits ADP-, thrombin-, and collagen-induced aggregation of human platelets (8). DFE differs from the antiplatelet activities found in other arthropods in two respects. First, it does not alter cAMP levels in platelets, suggesting that it does not contain prostaglandin-like activity. Second, it does not contain apyrase activity. We report the isolation and characterization of chrysopti...

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Section: Discussionmentioning

confidence: 99%

Chrysoptin Is a Potent Glycoprotein IIb/IIIa Fibrinogen Receptor Antagonist Present in Salivary Gland Extracts of the Deerfly

Reddy

Kounga

Mariano

et al. 2000

Journal of Biological Chemistry

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“…Integrins are a widely distributed superfamily of noncovalent heterodimeric glycoproteins that play a vital role in cellular adhesion, migration, and signal transduction (14,15). The ADAM disintegrin-like domains are homologous to small non-enzymatic peptides isolated from the venom of snakes that function as antagonists of integrins (16,17). The direct interaction of the snake venom disintegrin peptides with integrins led to the hypothesis that the disintegrin-like domains of ADAMs may function as integrin ligands.…”

mentioning

confidence: 99%

The Lymphocyte Metalloprotease MDC-L (ADAM 28) Is a Ligand for the Integrin α4β1

Bridges

Tani

Hanson

et al. 2002

Journal of Biological Chemistry

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A disintegrin and metalloprotease (ADAM) 1 is a family of recently identified cell surface and secreted glycoproteins that possess both proteolytic and adhesive properties (1, 2). Prototypical members of this family are composed of a prodomain, metalloprotease, disintegrin-like, cysteine-rich, EGF-like, transmembrane, and cytoplasmic domains. The metalloprotease domain is homologous to the reprolysins, members of the metazincin superfamily that include the matrix metalloproteases, the astacins, and serralysins (3). Although the ADAMs may serve other proteolytic functions, their role in the ectodomain shedding of specific cell surface proteins has been well documented (4, 5). ADAMs 9 (meltrin-␥), 10 (kuzbian), and 17 (tissue necrosis factor-␣-converting enzyme) have been shown to function in ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor, amyloid precursor protein, and tissue necrosis factor-␣, respectively (6 -10). These ADAMs and other members of this protein family have also been implicated in the shedding of other proteins such as L-selectin, FasL, and VCAM-1 (11-13). In addition to the proteolytic functions mentioned, several ADAMs have been shown to interact with the integrin family of cell surface receptors. Integrins are a widely distributed superfamily of noncovalent heterodimeric glycoproteins that play a vital role in cellular adhesion, migration, and signal transduction (14, 15). The ADAM disintegrin-like domains are homologous to small non-enzymatic peptides isolated from the venom of snakes that function as antagonists of integrins (16,17). The direct interaction of the snake venom disintegrin peptides with integrins led to the hypothesis that the disintegrin-like domains of ADAMs may function as integrin ligands. The disintegrin-like domains of ADAMs 1-3 expressed on the surface of sperm interact with the integrin ␣ 6 ␤ 1 in association with CD9 and CD98 on the egg surface (18 -23). Recognition of ADAMs 2 and 3 by ␣ 6 ␤ 1 requires the residues DECD located within a region of the disintegrin domain, designated the disintegrin loop, that corresponds to an extended loop in the snake venom peptides that typically contains an RGD sequence required for integrin binding (21-23). Human ADAM 15 contains an RGD sequence within the disintegrin loop region and is recognized by the integrins ␣ v ␤ 3 and ␣ 5 ␤ 1 (24 -26). However, mouse ADAM 15 lacks the RGD sequence found in the human homologue. Both human and mouse ADAM 15 as well as ADAM 12 were shown to be recognized by the integrin ␣ 9 ␤ 1 via residues outside the disintegrin loop (27). Other ADAM disintegrin-like domains reported to bind integrins are ADAM 9, which is recognized by ␣ 6 ␤ 1 and ␣ v ␤ 5 (28, 29), and ADAM 23, which is recognized by ␣ v ␤ 3 (30). * This work was supported by National Institutes of Health Grant AI47314. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section...

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“…RGD also appears to be the active epitope in most disintegrins (Gould et al, 1990). In this study, we detected various integrins (i.e.…”

Section: Tcipamentioning

confidence: 73%

The Arg-Gly-Asp-containing peptide, rhodostomin, inhibits in vitro cell adhesion to extracellular matrices and platelet aggregation caused by saos-2 human osteosarcoma cells

Chiang

Yang²,

Huang³

1995

Br J Cancer

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Sumary Saos-2 cells, derived from a primary human osteosarcoma, caused dose-dependent platelet aggregation in heparinised human platelet-rich plasma. Saos-2 tumour cell-induced platelet aggregation (TCIPA) was completely inhibited by hirudin but unaffected by apyrase. The cell suspension shortened the plasma recalcification times of normal, factor VIII-deficient and factor IX-deficient human plasmas in a dosedependent manner. However, the cell suspension did not affect the recalcification time of factor VII-deficient plasma. Moreover, a monoclonal antibody (MAb) against human tissue factor completely abolished TCIPA. Flow cytometric analysis using anti-integrin MAbs as the primary binding ligands demonstrated that the integrin receptors cvP3, 1 and ae8B were present on the surface of Saos-2 cells, which might mediate tumour cell adhesion to extracellular matrix. Rhodostomin, an Arg-Gly-Asp (RGD)-containing snake venom peptide which antagonises the binding of fibnrnogen to platelet membrane glycoprotein i1b/i11a, prevented Saos-2 TCIPA as well as tumour cell adhesion to vitronectin, fibronectin and collagen type I. Likewise, the synthetic peptide Gly-Arg-Gly-Asp-Ser (GRGDS) showed a similar effect. On a molar basis, rhodostomin was about 18 000 and 1000 times. respectively, more potent than GRGDS in inhibiting TCIPA and tumour cell adhesion.

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Disintegrins: A Family of Integrin Inhibitory Proteins from Viper Venoms

Cited by 477 publications

References 0 publications

Chrysoptin Is a Potent Glycoprotein IIb/IIIa Fibrinogen Receptor Antagonist Present in Salivary Gland Extracts of the Deerfly

Chrysoptin Is a Potent Glycoprotein IIb/IIIa Fibrinogen Receptor Antagonist Present in Salivary Gland Extracts of the Deerfly

The Lymphocyte Metalloprotease MDC-L (ADAM 28) Is a Ligand for the Integrin α4β1

The Arg-Gly-Asp-containing peptide, rhodostomin, inhibits in vitro cell adhesion to extracellular matrices and platelet aggregation caused by saos-2 human osteosarcoma cells

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