How are proteins recruited to focal adhesion sites2017-12-26T14:19:08+00:00

Sequential protein recruitment to focal adhesion sites?

The chronological order of protein recruitment into focal adhesions leads to the concept of sequential assembly. Accordingly, the exact composition of each elongating adhesions is dependent on their age. The dynamics of component recruitment within individual adhesions has been shown to depend on the rate of lamellipodial protrusion within a given area [1]. Adhesions initially contain αVβ3 integrins, talin, paxillin and low levels of vinculin and focal adhesion kinase (FAK) [2] (reviewed in [3]).

Among the early components, FAK is a well-established mechanotransducer [4], that can bind Src [5], become activated [6] and serves to phosphorylate scaffolding proteins such as paxillin [7] and p130Cas [8] (reviewed in [9]). It also suppresses Rho activity to promote adhesion turnover [10]. p130CAS, in turn, facilitates formation of Rac-GEF complex, leading to membrane protrusion and ruffling [11] (reviewed in [12]). Paxillin contains several protein interaction domains that bind to numerous signaling molecules (e.g. kinases, phosphatases, Rho family of GTPases), adhesion molecules (e.g. α-integrin [13][14]) and actin-binding proteins (e.g. vinculin and parvin)[15] (reviewed in [16]).

The recruitment of vinculin along with talin promotes the clustering of activated integrins, forming a flexible bridge between the receptors and the actin network [17][18]. Vinculin also contributes to mechanical stability by regulating contractile stress generation [19]. Thus, the later stages can be distinguished by the presence of higher levels of vinculin, α-actinin, FAK, VASP and low levels of zyxin (reviewed in [2]).

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References

  1. Zaidel-Bar R, Ballestrem C, Kam Z, and Geiger B. Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J. Cell. Sci. 2003; 116(Pt 22):4605-13. [PMID: 14576354]
  2. Zimerman B, Volberg T, and Geiger B. Early molecular events in the assembly of the focal adhesion-stress fiber complex during fibroblast spreading. Cell Motil. Cytoskeleton 2004; 58(3):143-59. [PMID: 15146534]
  3. Zaidel-Bar R, Cohen M, Addadi L, and Geiger B. Hierarchical assembly of cell-matrix adhesion complexes. Biochem. Soc. Trans. 2004; 32(Pt3):416-20. [PMID: 15157150]
  4. Schober M, Raghavan S, Nikolova M, Polak L, Pasolli HA, Beggs HE, Reichardt LF, and Fuchs E. Focal adhesion kinase modulates tension signaling to control actin and focal adhesion dynamics. J. Cell Biol. 2007; 176(5):667-80. [PMID: 17325207]
  5. Schaller MD, Hildebrand JD, and Parsons JT. Complex formation with focal adhesion kinase: A mechanism to regulate activity and subcellular localization of Src kinases. Mol. Biol. Cell 1999; 10(10):3489-505. [PMID: 10512882]
  6. Laird AD, Li G, Moss KG, Blake RA, Broome MA, Cherrington JM, and Mendel DB. Src family kinase activity is required for signal tranducer and activator of transcription 3 and focal adhesion kinase phosphorylation and vascular endothelial growth factor signaling in vivo and for anchorage-dependent and -independent growth of human tumor cells. Mol. Cancer Ther. 2003; 2(5):461-9. [PMID: 12748308]
  7. Mofrad MRK, Golji J, Abdul Rahim NA, and Kamm RD. Force-induced unfolding of the focal adhesion targeting domain and the influence of paxillin binding. Mech Chem Biosyst 2004; 1(4):253-65. [PMID: 16783922]
  8. Cary LA, Han DC, Polte TR, Hanks SK, and Guan JL. Identification of p130Cas as a mediator of focal adhesion kinase-promoted cell migration. J. Cell Biol. 1998; 140(1):211-21. [PMID: 9425168]
  9. Panetti TS. Tyrosine phosphorylation of paxillin, FAK, and p130CAS: effects on cell spreading and migration. Front. Biosci. 2002; 7:d143-50. [PMID: 11779709]
  10. Ren XD, Kiosses WB, Sieg DJ, Otey CA, Schlaepfer DD, and Schwartz MA. Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. J. Cell. Sci. 2000; 113 ( Pt 20):3673-8. [PMID: 11017882]
  11. Sharma A, and Mayer BJ. Phosphorylation of p130Cas initiates Rac activation and membrane ruffling. BMC Cell Biol. 2008; 9:50. [PMID: 18793427]
  12. Huveneers S, and Danen EHJ. Adhesion signaling - crosstalk between integrins, Src and Rho. J. Cell. Sci. 2009; 122(Pt 8):1059-69. [PMID: 19339545]
  13. Liu S, Kiosses WB, Rose DM, Slepak M, Salgia R, Griffin JD, Turner CE, Schwartz MA, and Ginsberg MH. A fragment of paxillin binds the alpha 4 integrin cytoplasmic domain (tail) and selectively inhibits alpha 4-mediated cell migration. J. Biol. Chem. 2002; 277(23):20887-94. [PMID: 11919182]
  14. Deakin NO, Bass MD, Warwood S, Schoelermann J, Mostafavi-Pour Z, Knight D, Ballestrem C, and Humphries MJ. An integrin-alpha4-14-3-3zeta-paxillin ternary complex mediates localised Cdc42 activity and accelerates cell migration. J. Cell. Sci. 2009; 122(Pt 10):1654-64. [PMID: 19401330]
  15. Nikolopoulos SN, and Turner CE. Actopaxin, a new focal adhesion protein that binds paxillin LD motifs and actin and regulates cell adhesion. J. Cell Biol. 2000; 151(7):1435-48. [PMID: 11134073]
  16. Deakin NO, and Turner CE. Paxillin comes of age. J. Cell. Sci. 2008; 121(Pt 15):2435-44. [PMID: 18650496]
  17. 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]
  18. Giannone G, Jiang G, Sutton DH, Critchley DR, and Sheetz MP. Talin1 is critical for force-dependent reinforcement of initial integrin-cytoskeleton bonds but not tyrosine kinase activation. J. Cell Biol. 2003; 163(2):409-19. [PMID: 14581461]
  19. Mierke CT, Kollmannsberger P, Zitterbart DP, Smith J, Fabry B, and Goldmann WH. Mechano-coupling and regulation of contractility by the vinculin tail domain. Biophys. J. 2007; 94(2):661-70. [PMID: 17890382]