Tetraspanins and vascular functions

Abstract

Tetraspanins are multiple membrane-spanning proteins that likely function as the organizers of membrane microdomains. Tetraspanins associate with other membrane-bound molecules such as cell-adhesion proteins, growth factor receptors, and Ig superfamily members and regulate key cellular processes such as adhesion, migration, and fusion. Tetraspanins are widely expressed in vascular and haematopoietic cells and are involved in both physiological and pathological processes related to angiogenesis, vascular injury, thrombosis, and haemostasis. A wide body of evidence suggests that tetraspanins directly regulate the development and functions of the vascular system and the pathogenesis of vascular diseases. This article reviews current understanding of the roles of tetraspanins in vascular functions.

Figure 1

Schematic drawing of the structure of tetraspanins. Tetraspanins are composed of four transmembrane, an intracellular N- and C-termini, and two extracellular (one shorter, EC1, and one longer, EC2) domains. The conserved motifs or residues featured by tetraspanins are denoted. Most tetraspanins contain four or six cysteine residues in EC2, and two of those are in a highly conserved ‘CCG’ motif. Most of tetraspanins have glycosylation sites in EC2 as indicated as the squares, while CD9 is glycosylated in EC1. In each tetraspanin, there are several cysteine residues proximal to the interface of the inner leaflet and cytosol, which are the sites for palmitoylation and characteristic strong polar residues in the transmembrane domains. Tetraspanins also contains ‘YXXΦ’ sorting motif in the C-terminal cytoplasmic domain. C, Cysteine; E, Glutamic acid; G, Glycine; Q, Glutamine; N, Aspargine; S, Serine; Y, Tyrosine; X, any aminoacid; Φ, Hydrophobic aminoacid.

Figure 2

Schematic drawing showing cellular functions of tetraspanins. Tetraspanins associate with integrins, Ig superfamily proteins, and other transmembrane proteins. Additionally, tetraspanins are in molecular complex with cytoplasmic proteins, such as syntenin-1 (s) and signalling molecules. Tetraspanin containing complexes are designated as ‘tetraspanin web’ or ‘tetraspanin enriched microdmians’ (TEM). In addition to serving as organizers at the plasma membrane, tetraspanins are also enriched in the intracellular vesicles. Trafficking of tetraspanins between various cellular compartments tightly regulates exocytosis and trafficking of their associated partners. Tetraspanins in conjunction with other membrane proteins regulate cell–extracellular matrix adhesion, cell–cell interactions, cell migration, and modulate intracellular signaling events. Tetraspanins regulate phenomena such as vascular injury response, angiogenesis, heterotypic cell contacts, and tumour invasion and metastasis.