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  • Review Article
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Tetraspanin functions and associated microdomains

Key Points

  • 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.

Abstract

Cell-surface proteins of the tetraspanin family are small, and often hidden by a canopy of tall glycoprotein neighbours in the cell membrane. Consequently, tetraspanins have been understudied and underappreciated, despite their presence on nearly all cell and tissue types. Important new genetic evidence has now emerged, and is bolstered by new insights into the cell biology, signalling and biochemistry of tetraspanins. These new findings provide a framework for better understanding of these mysterious molecules in the regulation of cellular processes, from signalling to motility.

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Figure 1: Structural features of tetraspanins.
Figure 2: Tetraspanin signalling.
Figure 3: Molecular interactions of tetraspanins.

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DATABASES

Entrez Gene

lbm

sun

Tsp68C

ytr

Swiss-Prot

CD9

CD37

CD53

CD63

CD81

CD82

CD151

LCK

RDS

ROM1

TM4SF2

TSP-15

FURTHER INFORMATION

Martin Hemler's laboratory

Glossary

ROD OUTER SEGMENTS

The portion of the rod photoreceptor cell between the inner segment and the pigment epithelial layer of the retina.

INTEGRINS

A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.

GANGLIOSIDES

Anionic glycosphingolipids that carry, in addition to other sugar residues, one or more sialic acid residues.

PALMITOYLATION

The post-translational S-acylation of proteins with palmitate.

ERYTHROID PROGENITORS

The precursors to erythrocytes (red blood cells).

ERYTHROPOIETIN

A glycoprotein hormone that stimulates stem cells in the bone marrow to transform into erythrocytes (red blood cells).

PLATELETS

The smallest blood cells, which are important in haemostasis and blood coagulation.

KERATINOCYTES

Epithelial cells of the skin that have differentiated to produce keratin. Keratinocytes are the predominant cell type in the epidermis of the skin.

HUMORAL IMMUNE SYSTEM

Mediates immunity in the body through antibodies present in the blood plasma, tissue fluid and lymph.

MONOCYTE

A large leukocyte with a horseshoe-shaped nucleus. Monocytes derive from pluripotent stem cells and become phagocytic macrophages when they enter tissues.

GIANT CELL

A large, multinucleate cell that is thought to result from the fusion of several macrophages.

MYELINATION

The process by which myelin — a protein produced by Schwann cells or oligodendrocytes — is ensheathed around the axons of vertebrate nerves.

AXOGLIAL PARANODAL JUNCTIONS

Specialized adhesion sites between the axolemma (the outer membrane covering an axon) and myelinating glial cells.

HYPODERMIS

A thin layer of cells — often syncytial — that underlie the cuticle in nematodes.

RNA INTERFERENCE

(RNAi). A form of post-transcriptional gene silencing in which expression or transfection of dsRNA induces degradation, by nucleases, of the homologous endogenous transcripts. This mimics the effect of the reduction, or loss, of gene activity.

NEUROMUSCULAR JUNCTION

(NMJ). The place of contact between the terminal of a motor neuron and the membrane of a muscle fibre. Nerve impulses are transmitted across the gap by diffusion of a transmitter.

G-PROTEIN-COUPLED RECEPTOR

(GPCR). A seven-helix transmembrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

HAEMOCYTES

Blood cells, particularly of insects and crustacea. They are similar in many respects to leukocytes, as they are phagocytic and are not involved in oxygen transport.

EXTRACELLULAR MATRIX

(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates various cellular functions.

CABLE FORMATION

When dispersed on the surface of Matrigel or other gelatinous substrate, cells exert force onto the substrate and subsequently migrate along lines of mechanical tension to form a pattern of intersecting cellular cables.

MATRIGEL

The extracellular matrix secreted by the Engelbrecht–Holm–Swarm mouse sarcoma cell line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and therefore resembles the basement membrane.

COSTAMERE

A myofibril attachment site that contains the protein vinculin and that forms one of the main linkage sites of the skeletal muscle cell.

SHEAR FLOW

When fluid flows through a tube or channel, velocity is zero at the wall, and maximal at the centre. This has a shearing effect on the fluid (and in the case of blood, any cells within the fluid or attached to the wall).

PDZ DOMAIN

A protein-interaction domain that often occurs in scaffolding proteins, and is named after the founding members of this protein family (PSD95, Discs large and ZO1).

RUFFLING

A process that is formed by the movement of lamellipodia that are in the dynamic process of folding back onto the cell body from which they previously extended.

RHO-FAMILY GTPASES

A subfamily of small (21 kDa) GTP-binding proteins that are related to Ras, and that regulate the cytoskeleton.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

(GEF). A protein that activates a specific small GTPase by catalysing the exchange of bound GDP for GTP.

HAPTOTACTIC CELL MIGRATION

The directed migration of cells along surfaces with gradients of immobilized factors.

IMMUNOGLOBULIN SUPERFAMILY

A large family of proteins that includes antibodies and adhesive transmembrane proteins. Their structure is characterized by 'immunoglobulin loops' that are formed by disulphide bonds.

COMPLEMENT

Nine interacting serum proteins (C1–C9) — mostly enzymes — that are activated in a coordinated way and participate in bacterial lysis and macrophage chemotaxis.

GLYCOSYLPHOSPHATIDYL-INOSITOL (GPI) ANCHOR

The function of this post-translational modification is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is composed of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol and is linked to the protein through an ethanolamine phosphate moiety.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). A complex of genetic loci in higher vertebrates that encodes a family of cellular antigens that allow the immune system to recognize self from non-self.

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Hemler, M. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6, 801–811 (2005). https://doi.org/10.1038/nrm1736

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