Tetraspanin functions and associated microdomains

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Abstract
Tetraspanins do not protrude far above the plasma membrane, and do not typically bind external ligands. Nonetheless, this large family of molecules (for example, there are 32 in mammals) has considerable functional importance. By organizing multimolecular membrane complexes, tetraspanins regulate cell migration, fusion and signalling events. Mammalian genetics has yielded new insights into tetraspanin functions. For example, CD151 contributes to normal kidney, skin and platelet function; peripherin/RDS and ROM-1 support retinal integrity; and TALLA-1/A15 is important for brain function. Other tetraspanins enable sperm–egg fusion (CD9), support nervous system development (CD9, CD81), regulate monocyte fusion (CD9, CD81) and contribute to T-cell proliferation (CD151, CD37, Tssc6, CD81). Additional definitive insights come from genetic analyses in other species. Drosophila melanogaster tetraspanins are linked to light-induced retinal degeneration and haemocyte proliferation. The first reported Caenorhabditis elegans tetraspanin mutation leads to a disrupted epidermis, and several fungal tetraspanins are linked to host leaf penetration. These results from non-mammalian species provide important clues regarding the functions of tetraspanins in mammals. Although the tetraspanins CD81 and CD151 do not affect integrin-dependent ligand binding and cell adhesion, they do markedly influence integrin-dependent adhesion strengthening. Such results strongly suggest that tetraspanins can modulate the cytoskeleton, but specific connections remain to be established. Antibodies to the tetraspanins CD9 and CD81 can reduce cell proliferation. In both cases, recruitment of phosphatidylinositol 4-kinase, activation of Shc, and activation of the extracellular signal-regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) pathway might underlie effects on proliferation. These same pathways might also link CD9 to apoptosis. CD151 and CD82 have also been linked to various signalling events, which could help to explain their effects on cell morphology, motility and tumour progression. Understanding the organization of tetraspanin-enriched microdomains (TEMs) is essential for understanding tetraspanin functions. At the core of TEMs are various direct protein–protein partnerships, both homophilic and heterophilic. These primary building blocks are then assembled into a larger network of secondary interactions, with protein palmitoylation having an important supporting role. TEMs are distinct from lipid rafts in terms of the identity of components, and sensitivity to temperature, cholesterol, detergents and protein palmitoylation.