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Integrins: masters and slaves of endocytic transport

Key Points

  • Studies of the molecular mechanisms of integrin endocytosis support a role for the alternative clathrin adaptor, disabled 2.

  • Integrin trafficking during cell migration and cytokinesis has defined spatiotemporal characteristics. Integrin endocytosis and exocytosis can contribute to either en masse movement across the cell or to spatial restriction in defined cellular regions.

  • Integrin trafficking has a role in cell signalling. This can occur by trafficking-mediated alterations in the signalling of integrins to Rho GTPases and by the ability of integrins to control the trafficking of receptor tyrosine kinases, such as vascular endothelial growth factor receptor 2 and epidermal growth factor 1.

  • Integrin trafficking also has a role in cancer. The trafficking of matrix receptors contributes to aberrant cytokinesis (RAB21 trafficking), invasive migration (Rab-coupling protein and RAB25 trafficking) and tumour angiogenesis.

  • During angiogenesis, the trafficking of integrins dictates the deposition of the extracellular matrix.

Abstract

Since it has become clear that adhesion receptors are trafficked through the endosomal pathway and that this can influence their function, much effort has been invested in obtaining detailed descriptions of the molecular machinery responsible for internalizing and recycling integrins. New findings indicate that integrin trafficking dictates the nature of Rho GTPase signalling during cytokinesis and cell migration. Furthermore, integrins can exert control over the trafficking of other receptors in a way that drives cancer cell invasion and tumour angiogenesis.

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Figure 1: Endocytosis of integrin heterodimers.
Figure 2: Organization of endocytic cargo during cell migration and cytokinesis.
Figure 3: Effects of integrin trafficking on Rho GTPase signalling.
Figure 4: Role of integrins in controlling lipid raft and receptor tyrosine kinase trafficking.

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Acknowledgements

J.C.N, P.T.C and S.V are supported by funding from Cancer Research UK.

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Glossary

Integrin

A member of a large family of transmembrane proteins that traverse the plasma membrane as heterodimers of α- and β-subunits. An important role for integrins is to mediate the interaction of cells with ECM components such as fibronectin, and with the intracellular cytoskeleton.

Extracellular matrix

(ECM). A network of secreted proteins (such as fibronectin and collagen) and polysaccharides that largely fills the extracellular milieu of many tissues and organs. The ECM provides structural support for cells and acts as a fulcrum on which cells must exert force to migrate.

Fibronectin

A high-molecular weight ECM glycoprotein that binds to integrins.

Focal adhesion

A large, dynamic protein complex in which the cytoskeleton of a cell connects to the ECM through integrins.

Dynamin

A GTPase that is responsible for endocytosis in the eukaryotic cell. Dynamin has been extensively studied with respect to clathrin-coated vesicle budding from the cell membrane.

Total internal reflection fluorescence microscopy

A type of microscopy that uses an evanescent field to illuminate a thin region of a specimen (usually less than 200 nm).

Perinuclear recycling compartment

A vesicular compartment that is located in the juxtanuclear region, often close to the microtubule organizing centre. Following endocytosis, many receptors are delivered here before returning to the plasma membrane. The RAB11 family of GTPases are commonly enriched in this compartment and are essential for its function and the maintenance of its morphology

Sorting endosome

The first station to which internalized cargo is delivered following the uncoating of endocytic vesicles. Endocytic cargo is triaged within the sorting endosome and then sent to numerous cellular destinations including multivesicular bodies and the perinuclear recycling compartment. Alternatively, some cargos may be returned directly to the plasma membrane.

Lamellipodium

A flat, actin-rich fan-shaped feature at the leading edge of some motile cells.

Pseudopod

A projection that emanates from cells and normally extends in the direction of migration. The term pseudopod is used here to describe a projection that is longer and thinner than a lamellipodium.

Cleavage furrow

The indentation that begins the process of cleavage and by which animal cells, and some algal cells, undergo cytokinesis.

Rab-coupling protein

(RCP). A member of the FIP family of RAB11-interacting proteins. It contains a domain responsible for interacting with RAB11 family members (including RAB11A, RAB11B and RAB25) and a C2 domain that has been shown to bind to membrane lipids such as phosphatidic acid. RCP is a key effector for RAB11 with regard to the trafficking of integrins.

Cilengitide

A cyclic peptide with the sequence cyclo-RGDfNmeV. Cilengitide is a high affinity antagonist of αvβ3 and αvβ5 integrins and was developed with the view to being a potential anti-angiogenic and anti-cancer drug.

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Caswell, P., Vadrevu, S. & Norman, J. Integrins: masters and slaves of endocytic transport. Nat Rev Mol Cell Biol 10, 843–853 (2009). https://doi.org/10.1038/nrm2799

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