Integrin Regulation in Immunological and Cancerous Cells and Exosomes

Abstract

Integrins represent the biologically and medically significant family of cell adhesion molecules that govern a wide range of normal physiology. The activities of integrins in cells are dynamically controlled via activation-dependent conformational changes regulated by the balance of intracellular activators, such as talin and kindlin, and inactivators, such as Shank-associated RH domain interactor (SHARPIN) and integrin cytoplasmic domain-associated protein 1 (ICAP-1). The activities of integrins are alternatively controlled by homotypic lateral association with themselves to induce integrin clustering and/or by heterotypic lateral engagement with tetraspanin and syndecan in the same cells to modulate integrin adhesiveness. It has recently emerged that integrins are expressed not only in cells but also in exosomes, important entities of extracellular vesicles secreted from cells. Exosomal integrins have received considerable attention in recent years, and they are clearly involved in determining the tissue distribution of exosomes, forming premetastatic niches, supporting internalization of exosomes by target cells and mediating exosome-mediated transfer of the membrane proteins and associated kinases to target cells. A growing body of evidence shows that tumor and immune cell exosomes have the ability to alter endothelial characteristics (proliferation, migration) and gene expression, some of these effects being facilitated by vesicle-bound integrins. As endothelial metabolism is now thought to play a key role in tumor angiogenesis, we also discuss how tumor cells and their exosomes pleiotropically modulate endothelial functions in the tumor microenvironment.

Keywords: angiogenesis; endothelial metabolism; exosome; integrin; kindlin; talin.

Figure 1

Conformational regulation of integrins on the cell surface. The inactive integrin adopts a closed conformation, in which the headpiece is folded back to the legpiece (right). Such an inactive integrin is stabilized by the association of the αβ cytoplasmic domain, which is strengthened by SHARPIN and ICAP-1. The binding of talin and kindlin induces dissociation of the αβ cytoplasmic domain, thereby triggering a global conformational change of the extracellular part to the active open integrin conformational state (middle). Tetraspanin associates with the integrin β subunit and modulates integrin activation. Extracellular ligation by cognate ligands and intracellular linkage to F-actin via talin facilitate the lateral association of integrin molecules, thereby enhancing cell adhesion.

Figure 2

Biogenesis of extracellular vesicles. Exosomes are formed by the endosomal pathway; in this manner, they are secreted to the extracellular space. Microvesicles are released directly from the plasma membrane. Functional integrins are present on the surface of exosomes and microvesicles.

Figure 3

Exosomal integrin-mediated remodeling of the homing niches of immune cells (left) and cancer cells (right).

Figure 4

Exosome-mediated remodeling of endothelial gene expression and metabolism. Exosomes derived from various kinds of cells, including tumor and immune cells, have the ability to alter the behavior, metabolism and gene expression in endothelial cells. (↑: increased; ↓: decreased)