Current Biology
Volume 11, Issue 18, 18 September 2001, Pages 1392-1402
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Research paper
PDGF-regulated rab4-dependent recycling of αvβ3 integrin from early endosomes is necessary for cell adhesion and spreading

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Abstract

Background: It has been postulated that the regulation of integrin vesicular traffic facilitates cell migration by internalizing integrins at the rear of the cell and transporting them forward within vesicles for exocytosis at the leading edge to form new contacts with the extracellular matrix. The rab family of GTPases control key targeting events in the endo/exocytic pathway; therefore, these GTPases may be involved in the regulation of cell-matrix contact assembly.

Results: The endo/exocytic cycle of αvβ3 and α5β1 integrins was studied using mouse 3T3 fibroblast cell lines. In serum-starved cells, internalized integrins were transported through rab4-positive, early endosomes and arrived at the rab11-positive, perinuclear recycling compartment approximately 30 min after endocytosis. From the recycling compartment, integrins were recycled to the plasma membrane in a rab11-dependent fashion. Following treatment with PDGF, αvβ3 integrin, but not α5β1, was rapidly recycled directly back to the plasma membrane from the early endosomes via a rab4-dependent mechanism without the involvement of rab11. This rapid recycling pathway directed αvβ3 to numerous small puncta distributed evenly across the dorsal surface of the cell, and the integrin only became localized into focal complexes at later times following PDGF addition. Interestingly, inhibition of PDGF-stimulated αvβ3 recycling using dominant-negative rab4 mutants compromised cell adhesion and spreading on vitronectin (a ligand for αvβ3), but adhesion to fibronectin (a ligand for α5β1 and αvβ3) was unchanged.

Conclusions: We propose that growth factor-regulated, rab4-dependent recycling of αvβ3 integrin from early endosomes to the plasma membrane is a critical upstream event in the assembly of cell-matrix contacts.

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Present address: Cancer & Infection, Astra Zeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom.