Mechanosignaling

How does integrin clustering affect integrin signaling?

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].

References

1. Santala P, and Heino J. Regulation of integrin-type cell adhesion receptors by cytokines. J. Biol. Chem. 1991; 266(34):23505-9. [PMID: 1744142]
2. Nishizaka T, Shi Q, and Sheetz MP. Position-dependent linkages of fibronectin- integrin-cytoskeleton. Proc. Natl. Acad. Sci. U.S.A. 2000; 97(2):692-7. [PMID: 10639141]
3. Puklin-Faucher E, and Sheetz MP. The mechanical integrin cycle. J. Cell. Sci. 2009; 122(Pt 2):179-86. [PMID: 19118210]
4. Ivaska J, Whelan RDH, Watson R, and Parker PJ. PKC epsilon controls the traffic of beta1 integrins in motile cells. EMBO J. 2002; 21(14):3608-19. [PMID: 12110574]
5. Barczyk M, Carracedo S, and Gullberg D. Integrins. Cell Tissue Res. 2009; 339(1):269-80. [PMID: 19693543]
6. Katagiri K, Maeda A, Shimonaka M, and Kinashi T. RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat. Immunol. 2003; 4(8):741-8. [PMID: 12845325]
7. Schvartzman M, Palma M, Sable J, Abramson J, Hu X, Sheetz MP, and Wind SJ. Nanolithographic control of the spatial organization of cellular adhesion receptors at the single-molecule level. Nano Lett. 2011; 11(3):1306-12. [PMID: 21319842]
8. Coyer SR, Singh A, Dumbauld DW, Calderwood DA, Craig SW, Delamarche E, and García AJ. Nanopatterning reveals an ECM area threshold for focal adhesion assembly and force transmission that is regulated by integrin activation and cytoskeleton tension. J. Cell. Sci. 2012; 125(Pt 21):5110-23. [PMID: 22899715]
9. Humphries JD, Wang P, Streuli C, Geiger B, Humphries MJ, and Ballestrem C. Vinculin controls focal adhesion formation by direct interactions with talin and actin. J. Cell Biol. 2007; 179(5):1043-57. [PMID: 18056416]
10. Saltel F, Mortier E, Hytönen VP, Jacquier M, Zimmermann P, Vogel V, Liu W, and Wehrle-Haller B. New PI(4,5)P2- and membrane proximal integrin-binding motifs in the talin head control beta3-integrin clustering. J. Cell Biol. 2009; 187(5):715-31. [PMID: 19948488]
11. Friedland JC, Lee MH, and Boettiger D. Mechanically activated integrin switch controls alpha5beta1 function. Science 2009; 323(5914):642-4. [PMID: 19179533]
12. Ginsberg MH, Partridge A, and Shattil SJ. Integrin regulation. Curr. Opin. Cell Biol. 2005; 17(5):509-16. [PMID: 16099636]
13. Yu C, Law JBK, Suryana M, Low HY, and Sheetz MP. Early integrin binding to Arg-Gly-Asp peptide activates actin polymerization and contractile movement that stimulates outward translocation. Proc. Natl. Acad. Sci. U.S.A. 2011; 108(51):20585-90. [PMID: 22139375]