Laminin-binding integrins and their tetraspanin partners as potential antimetastatic targets

Abstract

Within the integrin family of cell adhesion receptors, integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 make up a laminin-binding subfamily. The literature is divided on the role of these laminin-binding integrins in metastasis, with different studies indicating either pro- or antimetastatic functions. The opposing roles of the laminin-binding integrins in different settings might derive in part from their unusually robust associations with tetraspanin proteins. Tetraspanins organise integrins into multiprotein complexes within discrete plasma membrane domains termed tetraspanin-enriched microdomains (TEMs). TEM association is crucial to the strikingly rapid cell migration mediated by some of the laminin-binding integrins. However, emerging data suggest that laminin-binding integrins also promote the stability of E-cadherin-based cell-cell junctions, and that tetraspanins are essential for this function as well. Thus, TEM association endows the laminin-binding integrins with both pro-invasive functions (rapid migration) and anti-invasive functions (stable cell junctions), and the composition of TEMs in different cell types might help determine the balance between these opposing activities. Unravelling the tetraspanin control mechanisms that regulate laminin-binding integrins will help to define the settings where inhibiting the function of these integrins would be helpful rather than harmful, and may create opportunities to modulate integrin activity in more sophisticated ways than simple functional blockade.

Figure 1

Tetraspanin-enriched microdomains. Laminin-binding integrins associate directly with tetraspanin CD151 and are linked to other tetraspanins (such as CD9, CD63, CD81 and CD82) and tetraspanin partner proteins, such as the immunoglobulin superfamily proteins EWI-2 and EWI-F (the EWI proteins). Cytoplasmic effectors associated with tetraspanin-enriched microdomains (TEMs) include type II phosphatidylinositol 4-kinases (PI4KIIs), classical protein kinase C (PKC) isoforms, ezrin–radixin–moesin family proteins (ERMs), and AP adaptor proteins (APs). Key structural features of tetraspanins include large and small extracellular domains (EC2 and EC1, respectively), polar amino acid residues within transmembrane domains 1, 3 and 4, and palmitoylation of intracellular cysteine residues.

Figure 2

Consequences of TEM localisation for laminin-binding integrins. Laminin-binding integrins (represented by α3β1) associate with tetraspanin CD151 via a direct protein–protein interaction between the α integrin subunit ectodomain and the CD151 EC2 domain. The integrin–CD151 complex forms early in biosynthesis and is delivered to cell-surface tetraspanin-enriched microdomains (TEMs). TEM localisation may promote α3β1-dependent tumour cell migration on laminin-5 in multiple ways including (1) facilitating the formation of small, promigratory focal contacts, (2) participating in promigratory signalling, and (3) facilitating efficient internalisation of α3β1 at the trailing edge of migrating cells. TEM localisation may also allow α3β1 to collaborate with E-cadherin to reduce the activity of the RhoA small GTPase to a low basal level. Too much RhoA activity can destabilise adherens junctions, which normally function to restrain tumour cell motility. Thus, by keeping RhoA activity low, α3β1–tetraspanin complexes might exert an antimigratory activity that balances α3β1's promigratory functions.