How does integrin clustering affect integrin signalling?2017-12-26T14:40:00+08:30

How does integrin clustering affect integrin signalling?

Localization of Integrin

The concentration of β subunits is generally high while that of α subunit is the factor limiting the amount of heterodimers that localize on the membrane [1]. Liganded integrins diffuse along the membrane and are known to preferentially couple actin at the leading edge [2], cluster, get pulled backward as the cell spreads or moves forward and subsequently cycled during motility [3][4].

Integrins are found in specialized cell-cell adhesions and in most cell-matrix adhesions of static cells as well as motility structures such as filopodia, lamellipodia and podosomes. While the β1 subfamily is commonly found on a wide variety of cells, some integrins are limited to certain cell types or tissues [5] as listed in the table.

Integrin clustering

Clustering occurs by integrin diffusion, multivalent ligand binding leading to transmembrane homodimerization or inside-out signals. For example, in lymphocytes Rap1 GTPase and its effector RAPL (regulator for cell adhesion and polarization enriched in lymphoid tissues) have been shown to regulate patchy distribution of integrin LFA-1 [6]. Nanolithographic study provides strong evidence that controlled spatial organization of liganded integrins in nanoclusters is essential for effective signaling and is independent of global density [7]. Also, the minimum cluster area required for stable adhesion formation and force transduction is determined by the adhesive force, cytoskeletal tension and the force-transmitting structural linkage. Thus, it is not a constant and has a dynamic threshold [8].

Nanoclustering is driven by the interaction of N-terminal of vinculin with talin [9], which in turn is promoted by contractile forces. Some talin-integrin interactions are also essential to prevent re-association of the separated integrin tails and maintain the activated integrins in a clustering-competent form [10]. Increasing the avidity (valency) of ligand binding and clustering also contributes to adhesion strength and outside-in signaling [3][11].

Whether clustering triggers outside-in signalling to facilitate integrin activation, or whether clustering occurs after integrin activation has yet to be fully ascertained (reviewed in [12]). In one study, however the early clustering of integrins was observed after integrin was activated by its binding to Arg-Gly-Asp (RGD) peptides. In this case, clustering occurred in several phases. In the earliest phase integrin binding to RGD led to the recruitment of additional integrin molecules, as well as the recruitment of talin, paxillin and FAK. This occurred via lateral diffusion and capture independently of mechanical force [13]. In a later phase, following local actin polymerization and the recruitment of myosin, the aggregation of distant integrin clusters was observed. This resulted in larger adhesions, and was associated with the recruitment of vinculin and stimulation of a Src kinase-dependent lamellipodial extension. Here, the inward movement of integrin clusters was attributed to the generation of force following myosin-mediated retraction of actin filaments [13].

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