| First Author | Margadant C | Year | 2012 |
| Journal | Curr Biol | Volume | 22 |
| Issue | 17 | Pages | 1554-63 |
| PubMed ID | 22795696 | Mgi Jnum | J:199768 |
| Mgi Id | MGI:5504591 | Doi | 10.1016/j.cub.2012.06.060 |
| Citation | Margadant C, et al. (2012) Distinct roles of talin and kindlin in regulating integrin alpha5beta1 function and trafficking. Curr Biol 22(17):1554-63 |
| abstractText | BACKGROUND: Integrins are heterodimeric alphabeta 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 beta1 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 alpha5beta1 function and trafficking, we introduced Y > A mutations in either motif. Disruption of the membrane-proximal NPxY completely prevented alpha5beta1-induced morphological changes, cell scattering and migration, and fibronectin fibrillogenesis. In addition, it reduced alpha5beta1 internalization but not its recycling. In contrast, disruption of the membrane-distal NPxY promoted degradation of alpha5beta1 in late endosomes/lysosomes but did not prevent alpha5beta1-dependent cell scattering, migration, or fibronectin fibrillogenesis. Whereas depletion of either talin-1 or kindlin-2 reduced alpha5beta1 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 alpha5beta1 accumulation in lysosomes and degradation. CONCLUSIONS: The two NPxY motifs of beta1 play distinct and separable roles in controlling the function and trafficking of alpha5beta1. Whereas talin binding to the membrane-proximal NPxY is crucial for connecting alpha5beta1 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 alpha5beta1 surface expression and degradation. |
