Current Biology
Volume 22, Issue 17, 11 September 2012, Pages 1554-1563
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Article
Distinct Roles of Talin and Kindlin in Regulating Integrin α5β1 Function and Trafficking

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Summary

Background

Integrins are heterodimeric αβ transmembrane receptors that play key roles in cellular physiology and pathology. Accumulating data indicate that the two NPxY motifs in the cytoplasmic domain of the β1 subunit synergistically promote integrin activation through the binding of talin and kindlin. However, it is unclear how the individual motifs regulate integrin function and trafficking.

Results

To investigate how the two NPxY motifs individually control integrin α5β1 function and trafficking, we introduced Y > A mutations in either motif. Disruption of the membrane-proximal NPxY completely prevented α5β1-induced morphological changes, cell scattering and migration, and fibronectin fibrillogenesis. In addition, it reduced α5β1 internalization but not its recycling. In contrast, disruption of the membrane-distal NPxY promoted degradation of α5β1 in late endosomes/lysosomes but did not prevent α5β1-dependent cell scattering, migration, or fibronectin fibrillogenesis. Whereas depletion of either talin-1 or kindlin-2 reduced α5β1 binding to fibronectin and cell adhesion, talin-1 depletion recapitulated the loss-of-function phenotype of the membrane-proximal NPxY mutation, whereas kindlin-2 depletion induced α5β1 accumulation in lysosomes and degradation.

Conclusions

The two NPxY motifs of β1 play distinct and separable roles in controlling the function and trafficking of α5β1. Whereas talin binding to the membrane-proximal NPxY is crucial for connecting α5β1 to the actin cytoskeleton and thus permit the tension required for fibronectin fibrillogenesis and cell migration, kindlin binding to the membrane-distal NPxY is dispensable for these events but regulates α5β1 surface expression and degradation.

Highlights

► Talin-NPxY binding is required for α5β1-induced cell scattering and migration ► Kindlin-NPxY binding is dispensable for α5β1-induced scattering and migration ► The NPxY motifs have distinct functions in regulating α5β1 function and trafficking ► Lysosomal routing and α5β1 degradation do not prevent cell scattering or migration

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