Disintegrins: integrin selective ligands which activate integrin-coupled signaling and modulate leukocyte functions

Abstract

Extracellular matrix proteins and cell adhesion receptors (integrins) play essential roles in the regulation of cell adhesion and migration. Interactions of integrins with the extracellular matrix proteins lead to phosphorylation of several intracellular proteins such as focal adhesion kinase, activating different signaling pathways responsible for the regulation of a variety of cell functions, including cytoskeleton mobilization. Once leukocytes are guided to sites of infection, inflammation, or antigen presentation, integrins can participate in the initiation, maintenance, or termination of the immune and inflammatory responses. The modulation of neutrophil activation through integrinmediated pathways is important in the homeostatic control of the resolution of inflammatory states. In addition, during recirculation, T lymphocyte movement through distinct microenvironments is mediated by integrins, which are critical for cell cycle, differentiation and gene expression. Disintegrins are a family of low-molecular weight, cysteine-rich peptides first identified in snake venom, usually containing an RGD (Arg-Gly-Asp) motif, which confers the ability to selectively bind to integrins, inhibiting integrin-related functions in different cell systems. In this review we show that, depending on the cell type and the microenvironment, disintegrins are able to antagonize the effects of integrins or to act agonistically by activating integrinmediated signaling. Disintegrins have proven useful as tools to improve the understanding of the molecular events regulated by integrin signaling in leukocytes and prototypes in order to design therapies able to interfere with integrin-mediated effects.

Thyroid hormone inhibition in L6 myoblasts of IGF-I-mediated glucose uptake and proliferation: new roles for integrin αvβ3

“…Disintegrins have been considered to be antagonists of the receptor, although recent evidence indicates that they can have agonist effects on integrins (2,51). Our data suggest that echistatin is not exclusively an antagonist of integrin ␣v␤3 but that it may have a direct inhibitory effect on glucose uptake stimulated by IGF-I (Fig.…”

Importance of Snake Venom Metalloproteinases in Cell Biology: Effects on Platelets,Inflammatory and Endothelial Cells

“…Classical disintegrins, generated from P-II SVMPs processing, are also active on inflammatory cells, capable of activating integrinsignaling pathways, dependent on the cell type and on the surrounding environment encountered by a given cell [115]. Rhodostomin, an RGD-disintegrin isolated from Calloselasma rhodostoma venom, presented antiinflammatory properties as binding to neutrophils, in an RGD-dependent manner, blocking the adhesion of these cells to fibrinogen and attenuating their superoxide production [116].…”

Roles of Phosphatidylinositol 3-Kinase and NF-κB in Human Cytomegalovirus-Mediated Monocyte Diapedesis and Adhesion: Strategy for Viral Persistence

“…Integrins are recognized as the dominant cell adhesion receptors involved in firm adhesion of monocytes to endothelial cells and to extracellular matrix (ECM) components (3). Peripheral blood monocytes primarily express the ␤ 1 (CD29) and ␤ 2 (CD18) integrin subunits (13,15), which predominately form the following heterodimeric integrin molecules in monocytes: CD49d/CD29 (␣ 4 ␤ 1 ; VLA-4), CD49e/CD29 (␣ 5 ␤ 1 ; VLA-5), CD49f/CD29 (␣ 6 ␤ 1 ; VLA-6), CD11a/CD18 (␣ L ␤ 2 ; LFA-1), CD11b/CD18 (␣ M ␤ 2 ; Mac1; CR3), and CD11c/CD18 (␣ x ␤ 2 ; gp150/95) (15).…”