3 integrins (Nishimura et al., 2007; White et al., 2007). Suppression of β β Numb impairs clathrin-dependent integrin endocytosis, but to a lesser extent than suppression of AP2 and clathrin together, demonstrating that in addition to Numb, other clathrin-associated proteins such as Dab2 regulate integrin internalization (Nishimura Figure 10. Effect of integrin endocytosis on cell migration. A) Phosphorylation of Numb results in loss of Numb binding to integrin and subsequent loss of endocytosis, leading to directional persistent migration. B/C) Active recycling of 5 1 integrins results in random cell migration, while active recycling α β of v 3 integrins leads to directional persistent migration. (from Petrie et al., 2009) α β 22
et al., 2007). Like Numb, Dab2 also binds directly to the MD-NPxY motif of -tails; β according to one study binding does occur to β 3 and β 5 integrins, but not β 1A integrins, while binding to β 1 integrins was observed in two other studies (Calderwood et al., 2003; Teckchandani et al., 2009; Prunier & Howe, 2005). Dab-2 depletion leads to increased integrin surface expression, but reduction of the integrin intracellular pool. Reduced migration but not excess adhesion is observed in Dab2-deficient cells, and it is thought that maintenance of the intracellular integrin pool by Dab2 normally enables trafficking of integrins to the leading edge of the cell surface during cell migration to form new adhesion sites (Teckchandani et al., 2009). Numb and Dab2 differ in localization; whereas Numb localizes in FAs near CCSs at the leading edge, Dab2 is diffusely distributed over the cell surface (Nishimura et al., 2007; Teckchandani et al., 2009). In conclusion, integrins can follow different routes inside the cell, resulting in either recycling or degradation. It is likely that both active and inactive integrins can be internalized, although there may be some difference in the proteins involved in endocytosis. Since several studies give contradicting results, it remains unclear whether the NxxY motifs are important as internalization signals. 23
4 Discussion Integrins exist on the membrane in a conformation of low, intermediate, or high affinity for ligand, and the shift from low to high affinity is called integrin activation. This conformational change can occur from the inside, which is referred to as ‘inside-out’ signaling or activation. After ligand binding, integrins connect to the actin cytoskeleton, which is accompanied by the formation of adhesion plaques, cell spreading over the substrate, and the initiation of several signaling cascades (‘outside-in’ signaling). The paradigm of inside-out integrin activation has been developed mainly from studies on the platelet integrin IIb 3. Integrin IIb 3 and other integrins on non-adherent cells α β α β are ‘locked’ in the low-affinity conformation by a salt bridge between the cytoplasmic sequences of the - and the -subunits. Activation of IIb 3 occurs by GPCR agonists α β that trigger an intracellular pathway, of which the final step is talin binding to the -tail,
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