Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Integrin trafficking in cells and tissues

Abstract

Cell adhesion to the extracellular matrix is fundamental to metazoan multicellularity and is accomplished primarily through the integrin family of cell-surface receptors. Integrins are internalized and enter the endocytic–exocytic pathway before being recycled back to the plasma membrane. The trafficking of this extensive protein family is regulated in multiple context-dependent ways to modulate integrin function in the cell. Here, we discuss recent advances in understanding the mechanisms and cellular roles of integrin endocytic trafficking.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Composition and function of the integrin family.
Fig. 2: Fine-tuning integrin endocytosis and recycling.
Fig. 3: Integrin trafficking in development.

Similar content being viewed by others

References

  1. Humphries, J. D., Byron, A. & Humphries, M. J. Integrin ligands at a glance. J. Cell Sci. 119, 3901–3903 (2006).

    CAS  PubMed  Google Scholar 

  2. Maartens, A. P. & Brown, N. H. Anchors and signals: the diverse roles of integrins in development. Curr. Top. Dev. Biol. 112, 233–272 (2015).

    PubMed  Google Scholar 

  3. Mould, A. P. & Humphries, M. J. Regulation of integrin function through conformational complexity: not simply a knee-jerk reaction? Curr. Opin. Cell Biol. 16, 544–551 (2004).

    CAS  PubMed  Google Scholar 

  4. De Franceschi, N., Hamidi, H., Alanko, J., Sahgal, P. & Ivaska, J. Integrin traffic—the update. J. Cell Sci. 128, 839–852 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. Shattil, S. J., Kim, C. & Ginsberg, M. H. The final steps of integrin activation: the end game. Nat. Rev. Mol. Cell Biol. 11, 288–300 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kim, C., Ye, F. & Ginsberg, M. H. Regulation of integrin activation. Annu. Rev. Cell Dev. Biol. 27, 321–345 (2011).

    CAS  PubMed  Google Scholar 

  7. Legate, K. R. & Fassler, R. Mechanisms that regulate adaptor binding to β-integrin cytoplasmic tails. J. Cell Sci. 122, 187–198 (2009).

    CAS  PubMed  Google Scholar 

  8. Arjonen, A., Alanko, J., Veltel, S. & Ivaska, J. Distinct recycling of active and inactive β1 integrins. Traffic 13, 610–625 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nieswandt, B., Varga-Szabo, D. & Elvers, M. Integrins in platelet activation. J. Thromb. Haemost 7, 206–209 (2009).

    CAS  PubMed  Google Scholar 

  10. Bouvard, D., Pouwels, J., De Franceschi, N. & Ivaska, J. Integrin inactivators: balancing cellular functions in vitro and in vivo. Nat. Rev. Mol. Cell Biol. 14, 432–444 (2013).

    CAS  Google Scholar 

  11. Sun, Z., Costell, M. & Fassler, R. Integrin activation by talin, kindlin and mechanical forces. Nat. Cell Biol. (2019).

  12. Horton, E. R. et al. Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly. Nat. Cell Biol. 17, 1577–1587 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Horton, E. R. et al. The integrin adhesome network at a glance. J. Cell Sci. 129, 4159–4163 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Paul, N. R., Jacquemet, G. & Caswell, P. T. Endocytic trafficking of integrins in cell migration. Curr. Biol. 25, R1092–R1105 (2015).

    CAS  PubMed  Google Scholar 

  15. Valdembri, D. & Serini, G. Regulation of adhesion site dynamics by integrin traffic. Curr. Opin. Cell Biol. 24, 582–591 (2012).

    CAS  PubMed  Google Scholar 

  16. Alanko, J. et al. Integrin endosomal signalling suppresses anoikis. Nat. Cell Biol. 17, 1412–1421 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Nader, G. P. F., Ezratty, E. J. & Gundersen, G. G. FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly. Nat. Cell Biol. 18, 491–503 (2016).

    CAS  PubMed  Google Scholar 

  18. Ivaska, J. & Heino, J. Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu. Rev. Cell Dev. Biol. 27, 291–320 (2011).

    CAS  PubMed  Google Scholar 

  19. Barrow-McGee, R. et al. 1-integrin–c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes. Nat. Commun. 7, 11942 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Wilson, B. J., Allen, J. L. & Caswell, P. T. Vesicle trafficking pathways that direct cell migration in 3D and in vivo. Traffic. https://doi.org/10.1111/tra.12605 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhen, Y. & Stenmark, H. Cellular functions of Rab GTPases at a glance. J. Cell Sci. 128, 3171–3176 (2015).

    CAS  PubMed  Google Scholar 

  22. Lobert, V. H. et al. Ubiquitination of α5β1 integrin controls fibroblast migration through lysosomal degradation of fibronectin–integrin complexes. Dev. Cell 19, 148–159 (2010).

    CAS  PubMed  Google Scholar 

  23. Huet-Calderwood, C. et al. Novel ecto-tagged integrins reveal their trafficking in live cells. Nat. Commun. 8, 570 (2017).

    PubMed  PubMed Central  Google Scholar 

  24. Dozynkiewicz, M. A. et al. Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. Dev. Cell 22, 131–145 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bridgewater, R. E., Norman, J. C. & Caswell, P. T. Integrin trafficking at a glance. J. Cell Sci. 125, 3695–3701 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kaksonen, M. & Roux, A. Mechanisms of clathrin-mediated endocytosis. Nat. Rev. Mol. Cell Biol. 19, 313–326 (2018).

    CAS  PubMed  Google Scholar 

  27. Nishimura, T. & Kaibuchi, K. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev. Cell 13, 15–28 (2007).

    CAS  PubMed  Google Scholar 

  28. Ezratty, E. J., Partridge, M. A. & Gundersen, G. G. Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nat. Cell Biol. 7, 581–590 (2005).

    CAS  PubMed  Google Scholar 

  29. Ezratty, E. J., Bertaux, C., Marcantonio, E. E. & Gundersen, G. G. Clathrin mediates integrin endocytosis for focal adhesion disassembly in migrating cells. J. Cell Biol. 187, 733–747 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Eskova, A. et al. An RNAi screen identifies KIF15 as a novel regulator of the endocytic trafficking of integrin. J. Cell Sci. 127, 2433–2447 (2014).

    CAS  PubMed  Google Scholar 

  31. Atherton, P., Lausecker, F., Harrison, A. & Ballestrem, C. Low-intensity pulsed ultrasound promotes cell motility through vinculin-controlled Rac1 GTPase activity. J. Cell Sci. 130, 2277–2291 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lakshminarayan, R. et al. Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers. Nat. Cell Biol. 16, 592–603 (2014).

    Google Scholar 

  33. Doherty, G. J. et al. The endocytic protein GRAF1 is directed to cell–matrix adhesion sites and regulates cell spreading. Mol. Biol. Cell 22, 4380–4389 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bass, M. D. et al. A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis. Dev. Cell 21, 681–693 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. del Pozo, M. A. et al. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nat. Cell Biol. 7, 901–908 (2005).

    PubMed  PubMed Central  Google Scholar 

  36. Shi, F. & Sottile, J. Caveolin-1-dependent 1 integrin endocytosis is a critical regulator of fibronectin turnover. J. Cell Sci. 121, 2360–2371 (2008).

    CAS  PubMed  Google Scholar 

  37. Fabbri, M. et al. Dynamic partitioning into lipid rafts controls the endo-exocytic cycle of the αL2 integrin, LFA-1, during leukocyte chemotaxis. Mol. Biol. Cell 16, 5793–5803 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Gu, Z., Noss, E. H., Hsu, V. W. & Brenner, M. B. Integrins traffic rapidly via circular dorsal ruffles and macropinocytosis during stimulated cell migration. J. Cell Biol. 193, 61–70 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Pellinen, T. et al. Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of β1-integrins. J. Cell Biol. 173, 767–780 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Astro, V. et al. Liprin-α1 and ERC1 control cell edge dynamics by promoting focal adhesion turnover. Sci. Rep 6, 33653 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Astro, V., Chiaretti, S., Magistrati, E., Fivaz, M. & de Curtis, I. Liprin- 1, ERC1 and LL5 define polarized and dynamic structures that are implicated in cell migration. J. Cell Sci. 127, 3862–3876 (2014).

    CAS  PubMed  Google Scholar 

  42. Calderwood, D. A. et al. Integrin cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc. Natl Acad. Sci. USA 100, 2272–2277 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sandri, C. et al. The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. Cell Res. 22, 1479–1501 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Teckchandani, A. et al. Quantitative proteomics identifies a Dab2/integrin module regulating cell migration. J. Cell Biol. 186, 99–111 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Teckchandani, A., Mulkearns, E. E., Randolph, T. W., Toida, N. & Cooper, J. A. The clathrin adaptor Dab2 recruits EH domain scaffold proteins to regulate integrin 1 endocytosis. Mol. Biol. Cell 23, 2905–2916 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ramsay, A. G. et al. HS1-associated protein X-1 regulates carcinoma cell migration and invasion via clathrin-mediated endocytosis of integrin αvβ6. Cancer Res. 67, 5275–5284 (2007).

    CAS  PubMed  Google Scholar 

  47. De Franceschi, N. et al. Selective integrin endocytosis is driven by interactions between the integrin α-chain and AP2. Nat. Struct. Mol. Biol. 23, 172–179 (2016).

    PubMed  PubMed Central  Google Scholar 

  48. Yu, C. H. et al. Integrin-β3 clusters recruit clathrin-mediated endocytic machinery in the absence of traction force. Nat. Commun. 6, 8672 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Mygind, K. J., Schwarz, J., Sahgal, P., Ivaska, J. & Kveiborg, M. Loss of ADAM9 expression impairs β1 integrin endocytosis, focal adhesion formation and cancer cell migration. J. Cell Sci. 131, jcs205393 (2018).

    PubMed  Google Scholar 

  50. Morgan, M. R. et al. Syndecan-4 phosphorylation is a control point for integrin recycling. Dev. Cell 24, 472–485 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Mai, A. et al. Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1. J. Cell Sci. 127, 1938–1952 (2014).

    CAS  PubMed  Google Scholar 

  52. Hang, Q. et al. A key regulator of cell adhesion: identification and characterization of important N-glycosylation sites on integrin α5 for cell migration. Mol. Cell. Biol. 37, e00558–16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Caswell, P. T. et al. Rab25 associates with α5β1 integrin to promote invasive migration in 3D microenvironments. Dev. Cell 13, 496–510 (2007).

    CAS  PubMed  Google Scholar 

  54. Sun, L. et al. Rab34 regulates adhesion, migration, and invasion of breast cancer cells. Oncogene 37, 3698–3714 (2018).

    CAS  PubMed  Google Scholar 

  55. Argenzio, E. et al. CLIC4 regulates cell adhesion and 1 integrin trafficking. J. Cell Sci. 127, 5189–5203 (2014).

    PubMed  Google Scholar 

  56. Allaire, P. D. et al. Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell adhesion and migration. J. Cell Sci. 126, 722–731 (2013).

    CAS  PubMed  Google Scholar 

  57. Riggs, K. A. et al. Regulation of integrin endocytic recycling and chemotactic cell migration by syntaxin 6 and VAMP3 interaction. J. Cell Sci. 125, 3827–3839 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Tiwari, A. et al. Endothelial cell migration on fibronectin is regulated by syntaxin 6-mediated α5β1 integrin recycling. J. Biol. Chem. 286, 36749–36761 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Shafaq-Zadah, M. et al. Persistent cell migration and adhesion rely on retrograde transport of β1 integrin. Nat. Cell Biol. 18, 54–64 (2016).

    CAS  PubMed  Google Scholar 

  60. McNally, K. E. et al. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. Cell Biol. 19, 1214–1225 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Böttcher, R. T. et al. Sorting nexin 17 prevents lysosomal degradation of β1 integrins by binding to the β1-integrin tail. Nat. Cell Biol. 14, 584–592 (2012).

    PubMed  Google Scholar 

  62. Steinberg, F., Heesom, K. J., Bass, M. D. & Cullen, P. J. SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways. J. Cell Biol. 197, 219–230 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ratcliffe, C. D. H., Sahgal, P., Parachoniak, C. A., Ivaska, J. & Park, M. Regulation of cell migration and β1 integrin trafficking by the endosomal adaptor GGA3. Traffic 17, 670–688 (2016).

    CAS  PubMed  Google Scholar 

  64. Diggins, N. L., Kang, H., Weaver, A. & Webb, D. J. α5β1 integrin trafficking and Rac activation are regulated by APPL1 in a Rab5-dependent manner to inhibit cell migration. J. Cell Sci. 131, jcs207019 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Sahgal, P. et al. GGA2 and RAB13 regulate activity-dependent β1-integrin recycling. Preprint at https://www.biorxiv.org/content/early/2018/06/22/353086 (2018).

  66. Perini, E. D., Schaefer, R., Stöter, M., Kalaidzidis, Y. & Zerial, M. Mammalian CORVET is required for fusion and conversion of distinct early endosome subpopulations. Traffic 15, 1366–1389 (2014).

    CAS  PubMed  Google Scholar 

  67. Jonker, C. T. H. et al. Vps3 and Vps8 control integrin trafficking from early to recycling endosomes and regulate integrin-dependent functions. Nat. Commun. 9, 792 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Zech, T. et al. The Arp2/3 activator WASH regulates α5β1-integrin-mediated invasive migration. J. Cell Sci. 124, 3753–3759 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Jacquemet, G., Humphries, M. J. & Caswell, P. T. Role of adhesion receptor trafficking in 3D cell migration. Curr. Opin. Cell Biol. 25, 627–632 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Mana, G. et al. PPFIA1 drives active α5β1 integrin recycling and controls fibronectin fibrillogenesis and vascular morphogenesis. Nat. Commun. 7, 13546 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Hamidi, H. & Ivaska, J. Vascular morphogenesis: an integrin and fibronectin highway. Curr. Biol. 27, R158–R161 (2017).

    CAS  PubMed  Google Scholar 

  72. Rainero, E. Extracellular matrix internalization links nutrient signalling to invasive migration. Int. J. Exp. Pathol. 99, 4–9 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bridgewater, R. E., Streuli, C. H. & Caswell, P. T. Extracellular matrix promotes clathrin-dependent endocytosis of prolactin and STAT5 activation in differentiating mammary epithelial cells. Sci. Rep. 7, 4572 (2017).

    PubMed  PubMed Central  Google Scholar 

  74. Du, J. et al. Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity. Proc. Natl Acad. Sci. USA 108, 9466–9471 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Caswell, P. & Norman, J. Endocytic transport of integrins during cell migration and invasion. Trends Cell Biol 18, 257–263 (2008).

    CAS  PubMed  Google Scholar 

  76. Hamidi, H., Pietilä, M. & Ivaska, J. The complexity of integrins in cancer and new scopes for therapeutic targeting. Br. J. Cancer 115, 1017–1023 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Meighan, C. M. & Schwarzbauer, J. E. Temporal and spatial regulation of integrins during development. Curr. Opin. Cell Biol. 20, 520–524 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Akhtar, N. & Streuli, C. H. An integrin–ILK–microtubule network orients cell polarity and lumen formation in glandular epithelium. Nat. Cell Biol. 15, 17–27 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bryant, D. M. & Mostov, K. E. From cells to organs: building polarized tissue. Nat. Rev. Mol. Cell Biol. 9, 887–901 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Lee, J. L. & Streuli, C. H. Integrins and epithelial cell polarity. J. Cell Sci. 127, 3217–3225 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Bedzhov, I. & Zernicka-Goetz, M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell 156, 1032–1044 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Shahbazi, M. N. & Zernicka-Goetz, M. Deconstructing and reconstructing the mouse and human early embryo. Nat. Cell Biol. 20, 878–887 (2018).

    CAS  PubMed  Google Scholar 

  84. Bogdanović, O. et al. Numb/Numbl–Opo antagonism controls retinal epithelium morphogenesis by regulating integrin endocytosis. Dev. Cell 23, 782–795 (2012).

    PubMed  Google Scholar 

  85. Martinez-Morales, J. R. et al. Ojoplano-mediated basal constriction is essential for optic cup morphogenesis. Development 136, 2165–2175 (2009).

    CAS  PubMed  Google Scholar 

  86. Valdembri, D. et al. Neuropilin-1/GIPC1 signaling regulates α5β1 integrin traffic and function in endothelial cells. PLoS Biol. 7, e25 (2009).

    PubMed  Google Scholar 

  87. Hakanpaa, L. et al. Endothelial destabilization by angiopoietin-2 via integrin β1 activation. Nat. Commun. 6, 5962 (2015).

    CAS  PubMed  Google Scholar 

  88. Hakanpaa, L. et al. Targeting β1-integrin inhibits vascular leakage in endotoxemia. Proc. Natl Acad. Sci. USA 115, E6467–E6476 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Georgiadou, M. et al. AMPK negatively regulates tensin-dependent integrin activity. J. Cell Biol. 216, 1107–1121 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Rainero, E. et al. Ligand-occupied integrin internalization links nutrient signaling to invasive migration. Cell Rep 10, 398–413 (2015).

    CAS  PubMed  Google Scholar 

  91. Goreczny, G. J., Forsythe, I. J. & Turner, C. E. Hic-5 regulates fibrillar adhesion formation to control tumor extracellular matrix remodeling through interaction with tensin1. Oncogene 37, 1699–1713 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Muranen, T. et al. Starved epithelial cells uptake extracellular matrix for survival. Nat. Commun. 8, 13989 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Georgiadou, M. & Ivaska, J. Tensins: bridging AMP-activated protein kinase with integrin activation. Trends Cell Biol 27, 703–711 (2017).

    CAS  PubMed  Google Scholar 

  94. Yuan, L., Fairchild, M. J., Perkins, A. D. & Tanentzapf, G. Analysis of integrin turnover in fly myotendinous junctions. J. Cell Sci. 123, 939–946 (2010).

    CAS  PubMed  Google Scholar 

  95. Pines, M. et al. Mechanical force regulates integrin turnover in Drosophila in vivo. Nat. Cell Biol. 14, 935–943 (2012).

    CAS  PubMed  Google Scholar 

  96. López-Ceballos, P., Herrera-Reyes, A. D., Coombs, D. & Tanentzapf, G. In vivo regulation of integrin turnover by outside-in activation. J. Cell Sci. 129, 2912–2924 (2016).

    PubMed  Google Scholar 

  97. Wallroth, A. & Haucke, V. Phosphoinositide conversion in endocytosis and the endolysosomal system. J. Biol. Chem. 293, 1526–1535 (2018).

    CAS  PubMed  Google Scholar 

  98. Ribeiro, I., Yuan, L., Tanentzapf, G., Dowling, J. J. & Kiger, A. Phosphoinositide regulation of integrin trafficking required for muscle attachment and maintenance. PLoS Genet. 7, e1001295 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Ketel, K. et al. A phosphoinositide conversion mechanism for exit from endosomes. Nature 529, 408–412 (2016).

    CAS  PubMed  Google Scholar 

  100. Brower, D. L. Platelets with wings: the maturation of Drosophila integrin biology. Curr. Opin. Cell Biol. 15, 607–613 (2003).

    CAS  PubMed  Google Scholar 

  101. Bhuin, T. & Roy, J. K. Rab11 is required for cell adhesion, maintenance of cell shape and actin-cytoskeleton organization during Drosophila wing development. Int. J. Dev. Biol. 55, 269–279 (2011).

    CAS  PubMed  Google Scholar 

  102. Tsunoyama, T. A. et al. Super-long single-molecule tracking reveals dynamic-anchorage-induced integrin function. Nat. Chem. Biol. 14, 497–506 (2018).

    CAS  PubMed  Google Scholar 

  103. Hogg, N., Patzak, I. & Willenbrock, F. The insider’s guide to leukocyte integrin signalling and function. Nat. Rev. Immunol. 11, 416–426 (2011).

    CAS  PubMed  Google Scholar 

  104. Strachan, L. R. & Condic, M. L. Cranial neural crest recycle surface integrins in a substratum-dependent manner to promote rapid motility. J. Cell Biol. 167, 545–554 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Spicer, E., Suckert, C., Al-Attar, H. & Marsden, M. Integrin α5β1 function is regulated by XGIPC/kermit2 mediated endocytosis during Xenopus laevis gastrulation. PLoS ONE 5, e10665 (2010).

    PubMed  PubMed Central  Google Scholar 

  106. Lilja, J. & Ivaska, J. Integrin activity in neuronal connectivity. J. Cell Sci. 131, jcs212803 (2018).

    PubMed  Google Scholar 

  107. Clegg, D. O., Wingerd, K. L., Hikita, S. T. & Tolhurst, E. C. Integrins in the development, function and dysfunction of the nervous system. Front. Biosci. 8, d723–d750 (2003).

    CAS  PubMed  Google Scholar 

  108. Franco, S. J. & Müller, U. Extracellular matrix functions during neuronal migration and lamination in the mammalian central nervous system. Dev. Neurobiol. 71, 889–900 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Frick, A. et al. Proper cerebellar development requires expression of β1-integrin in Bergmann glia, but not in granule neurons. Glia 60, 820–832 (2012).

    PubMed  Google Scholar 

  110. Myers, J. P., Santiago-Medina, M. & Gomez, T. M. Regulation of axonal outgrowth and pathfinding by integrin–ECM interactions. Dev. Neurobiol. 71, 901–923 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Wojnacki, J. & Galli, T. Membrane traffic during axon development. Dev. Neurobiol. 76, 1185–1200 (2016).

    PubMed  Google Scholar 

  112. Eva, R. et al. ARF6 directs axon transport and traffic of integrins and regulates axon growth in adult DRG neurons. J. Neurosci. 32, 10352–10364 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Eva, R. et al. Rab11 and its effector Rab coupling protein contribute to the trafficking of β1 integrins during axon growth in adult dorsal root ganglion neurons and PC12 cells. J. Neurosci. 30, 11654–11669 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Falk, J., Konopacki, F. A., Zivraj, K. H. & Holt, C. E. Rab5 and Rab4 regulate axon elongation in the Xenopus visual system. J. Neurosci. 34, 373–391 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Koseki, H. et al. Selective Rab11 transport and the intrinsic regenerative ability of CNS axons. eLife 6, e26956 (2017).

    PubMed  PubMed Central  Google Scholar 

  116. Nieuwenhuis, B., Haenzi, B., Andrews, M. R., Verhaagen, J. & Fawcett, J. W. Integrins promote axonal regeneration after injury of the nervous system. Biol. Rev. 93, 1339–1362 (2018).

    PubMed  Google Scholar 

  117. Rehberg, K. et al. The serine/threonine kinase Ndr2 controls integrin trafficking and integrin-dependent neurite growth. J. Neurosci. 34, 5342–5354 (2014).

    PubMed  PubMed Central  Google Scholar 

  118. Das, L. et al. Characterization of laminin binding integrin internalization in prostate cancer cells. J. Cell. Biochem. 118, 1038–1049 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Spiess, M. et al. Active and inactive β1 integrins segregate into distinct nanoclusters in focal adhesions. J. Cell Biol. 217, 1929–1940 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Eisler, S.A. et al. A Rho signaling network links microtubules to PKD controlled carrier transport to focal adhesions. eLife 7, e35907 (2018).

    PubMed  PubMed Central  Google Scholar 

  121. De Franceschi, N. et al. ProLIF—quantitative integrin protein–protein interactions and synergistic membrane effects on proteoliposomes. J. Cell Sci. 132, jcs214270 (2018).

    PubMed  PubMed Central  Google Scholar 

  122. Streicher, P. et al. Integrin reconstituted in GUVs: a biomimetic system to study initial steps of cell spreading. Biochim. Biophys. Acta 1788, 2291–2300 (2009).

    CAS  PubMed  Google Scholar 

  123. Man, Y. K. S. et al. The novel oncolytic adenoviral mutant Ad5–3Δ-A20T retargeted to αvβ6 integrins efficiently eliminates pancreatic cancer cells. Mol. Cancer Ther. 17, 575–587 (2018).

    CAS  PubMed  Google Scholar 

  124. Rainero, E. & Norman, J. C. Late endosomal and lysosomal trafficking during integrin-mediated cell migration and invasion: cell matrix receptors are trafficked through the late endosomal pathway in a way that dictates how cells migrate. BioEssays 35, 523–532 (2013).

    CAS  PubMed  Google Scholar 

  125. Wang, Y. et al. Formin-like 2 promotes β1-integrin trafficking and invasive motility downstream of PKCα. Dev. Cell 34, 475–483 (2015).

    PubMed  Google Scholar 

  126. Hines, J. H., Abu-Rub, M. & Henley, J. R. Asymmetric endocytosis and remodeling of β1-integrin adhesions during growth cone chemorepulsion by MAG. Nat. Neurosci. 13, 829–837 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Palamidessi, A. et al. The GTPase-activating protein RN-tre controls focal adhesion turnover and cell migration. Curr. Biol. 23, 2355–2364 (2013).

    CAS  PubMed  Google Scholar 

  128. Qu, F. et al. Ankyrin-B is a PI3P effector that promotes polarized α5β1-integrin recycling via recruiting RabGAP1L to early endosomes. eLife 5, e20417 (2016).

    PubMed  PubMed Central  Google Scholar 

  129. Maekawa, M. et al. Cullin-3 and its adaptor protein ANKFY1 determine the surface level of integrin β1 in endothelial cells. Biol. Open 6, 1707–1719 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Theret, L. et al. Identification of LRP-1 as an endocytosis and recycling receptor for β1-integrin in thyroid cancer cells. Oncotarget 8, 78614–78632 (2017).

    PubMed  PubMed Central  Google Scholar 

  131. Wujak, L. et al. Low density lipoprotein receptor-related protein 1 couples β1 integrin activation to degradation. Cell. Mol. Life Sci. 75, 1671–1685 (2018).

    CAS  PubMed  Google Scholar 

  132. Margiotta, A., Progida, C., Bakke, O. & Bucci, C. Rab7a regulates cell migration through Rac1 and vimentin. Biochim. Biophys. Acta Mol. Cell Res 1864, 367–381 (2017).

    CAS  PubMed  Google Scholar 

  133. Das, L. et al. Novel regulation of integrin trafficking by Rab11–FIP5 in aggressive prostate cancer. Mol. Cancer Res. 16, 1319–1331 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Hülsbusch, N., Solis, G. P., Katanaev, V. L. & Stuermer, C. A. O. Reggie-1/flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a. Eur. J. Cell Biol. 94, 531–545 (2015).

    PubMed  Google Scholar 

  135. Icha, J., Weber, M., Waters, J. C. & Norden, C. Phototoxicity in live fluorescence microscopy, and how to avoid it. BioEssays 39, 1700003 (2017).

    Google Scholar 

  136. Laissue, P. P., Alghamdi, R. A., Tomancak, P., Reynaud, E. G. & Shroff, H. Assessing phototoxicity in live fluorescence imaging. Nat. Methods 14, 657–661 (2017).

    CAS  PubMed  Google Scholar 

  137. Liu, T. L. et al. Observing the cell in its native state: imaging subcellular dynamics in multicellular organisms. Science 360, eaaq1392 (2018).

    PubMed  PubMed Central  Google Scholar 

  138. Picco, A. & Kaksonen, M. Quantitative imaging of clathrin-mediated endocytosis. Curr. Opin. Cell Biol. 53, 105–110 (2018).

    CAS  PubMed  Google Scholar 

  139. Elkhatib, N. et al. Tubular clathrin/AP-2 lattices pinch collagen fibers to support 3D cell migration. Science 356, eaal4713 (2017).

    PubMed  Google Scholar 

  140. Nordenfelt, P. et al. Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration. Nat. Commun. 8, 2047 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. Martineau, M. et al. Semisynthetic fluorescent pH sensors for imaging exocytosis and endocytosis. Nat. Commun. 8, 1412 (2017).

    PubMed  PubMed Central  Google Scholar 

  142. Wood, L. A., Larocque, G., Clarke, N. I., Sarkar, S. & Royle, S. J. New tools for hot-wiring clathrin-mediated endocytosis with temporal and spatial precision. J. Cell Biol. 216, 4351–4365 (2017).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to all colleagues whose work was not mentioned here owing to space limitations. Work in the authors’ laboratory was supported by funding from the Academy of Finland, an ERC Consolidator Grant (no. 615258), the Sigrid Juselius Foundation and the Cancer Society of Finland. J.Icha is a member of the Turku Collegium of Science and Medicine and recipient of the EMBO Long-Term Fellowship ALTF 405-2018.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Johanna Ivaska.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moreno-Layseca, P., Icha, J., Hamidi, H. et al. Integrin trafficking in cells and tissues. Nat Cell Biol 21, 122–132 (2019). https://doi.org/10.1038/s41556-018-0223-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41556-018-0223-z

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing