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Cited by 32Cellular Mechanics and InteractionsMicrotubule and mitosis dynamicsCell Adhesion Molecules Research

Focal adhesions are controlled by microtubules through local contractility regulation

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Aureille, Julien, Prabhu, Srinivas S, Barnett, Sam F, Farrugia, Aaron J, Arnal, Isabelle, Lafanechère, Laurence, Low, Boon Chuan, Kanchanawong, Pakorn +2 more·2024·The EMBO Journal
DOI 10.1038/s44318-024-00114-4PMC PMC11217342

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Abstract

Microtubules regulate cell polarity and migration via local activation of focal adhesion turnover, but the mechanism of this process is insufficiently understood. Molecular complexes containing KANK family proteins connect microtubules with talin, the major component of focal adhesions. Here, local optogenetic activation of KANK1-mediated microtubule/talin linkage promoted microtubule targeting to an individual focal adhesion and subsequent withdrawal, resulting in focal adhesion centripetal sliding and rapid disassembly. This sliding is preceded by a local increase of traction force due to accumulation of myosin-II and actin in the proximity of the focal adhesion. Knockdown of the Rho activator GEF-H1 prevented development of traction force and abolished sliding and disassembly of focal adhesions upon KANK1 activation. Other players participating in microtubule-driven, KANK-dependent focal adhesion disassembly include kinases ROCK, PAK, and FAK, as well as microtubules/focal adhesion-associated proteins kinesin-1, APC, and αTAT. Based on these data, we develop a mathematical model for a microtubule-driven focal adhesion disruption involving local GEF-H1/RhoA/ROCK-dependent activation of contractility, which is consistent with experimental data.

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Research works printed but not linked: 59

  1. Applegate KT, Besson S, Matov A, Bagonis MH, Jaqaman K, Danuser G (2011) plusTipTracker: quantitative image analysis software for the measurement of microtubule dynamics. J Struct Biol 176:168–184 21821130 PMC3298692 · DOI
  2. Astro V, Tonoli D, Chiaretti S, Badanai S, Sala K, Zerial M, de Curtis I (2016) Liprin-alpha1 and ERC1 control cell edge dynamics by promoting focal adhesion turnover. Sci Rep 6:33653 27659488 PMC5034239 · DOI
  3. Azoitei ML, Noh J, Marston DJ, Roudot P, Marshall CB, Daugird TA, Lisanza SL, Sandi MJ, Ikura M, Sondek J et al (2019) Spatiotemporal dynamics of GEF-H1 activation controlled by microtubule- and Src-mediated pathways. J Cell Biol 218:3077–3097 31420453 PMC6719461 · DOI · Paper page
  4. Balaban NQ, Schwarz US, Riveline D, Goichberg P, Tzur G, Sabanay I, Mahalu D, Safran S, Bershadsky A, Addadi L et al (2001) Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nat Cell Biol 3:466–472 11331874 · DOI
  5. Beningo KA, Dembo M, Kaverina I, Small JV, Wang Y-L (2001) Nascent focal adhesions are responsible for the generation of strong propulsive forces in migrating fibroblasts. J Cell Biol 153:881–888 11352946 PMC2192381 · DOI
  6. Bershadsky A, Chausovsky A, Becker E, Lyubimova A, Geiger B (1996) Involvement of microtubules in the control of adhesion-dependent signal transduction. Curr Biol 6:1279–1289 8939572 · DOI
  7. Bhatt A, Kaverina I, Otey C, Huttenlocher A (2002) Regulation of focal complex composition and disassembly by the calcium-dependent protease calpain. J Cell Sci 115:3415–3425 12154072 · DOI
  8. Bouchet BP, Gough RE, Ammon YC, van de Willige D, Post H, Jacquemet G, Altelaar AM, Heck AJ, Goult BT, Akhmanova A (2016) Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions. Elife 5:e18124 27410476 PMC4995097 · DOI
  9. Chang YC, Nalbant P, Birkenfeld J, Chang ZF, Bokoch GM (2008) GEF-H1 couples nocodazole-induced microtubule disassembly to cell contractility via RhoA. Mol Biol Cell 19:2147–2153 18287519 PMC2366883 · DOI
  10. Chen Y, Pasapera AM, Koretsky AP, Waterman CM (2013) Orientation-specific responses to sustained uniaxial stretching in focal adhesion growth and turnover. Proc Natl Acad Sci USA 110:E2352–2361 23754369 PMC3696741
  11. Chorev DS, Moscovitz O, Geiger B, Sharon M (2014) Regulation of focal adhesion formation by a vinculin-Arp2/3 hybrid complex. Nat Commun 5:3758 24781749 · DOI
  12. Chrzanowska-Wodnicka M, Burridge K (1996) Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol 133:1403–1415 8682874 PMC2120895 · DOI
  13. Doss BL, Pan M, Gupta M, Grenci G, Mege RM, Lim CT, Sheetz MP, Voituriez R, Ladoux B (2020) Cell response to substrate rigidity is regulated by active and passive cytoskeletal stress. Proc Natl Acad Sci USA 117:12817–12825 32444491 PMC7293595 · DOI
  14. Efimov A, Kaverina I (2009) Significance of microtubule catastrophes at focal adhesion sites. Cell Adh Migr 3:285–287 19483470 PMC2712812 · DOI
  15. Etienne-Manneville S (2013) Microtubules in cell migration. Annu Rev Cell Dev Biol 29:471–499 23875648 · DOI
  16. Even-Ram S, Doyle AD, Conti MA, Matsumoto K, Adelstein RS, Yamada KM (2007) Myosin IIA regulates cell motility and actomyosin-microtubule crosstalk. Nat Cell Biol 9:299–309 17310241 · DOI
  17. Ezratty EJ, Partridge MA, Gundersen GG (2005) Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nat Cell Biol 7:581–590 15895076 · DOI
  18. Guntas G, Hallett RA, Zimmerman SP, Williams T, Yumerefendi H, Bear JE, Kuhlman B (2015) Engineering an improved light-induced dimer (iLID) for controlling the localization and activity of signaling proteins. Proc Natl Acad Sci USA 112:112–117 25535392 PMC4291625 · DOI
  19. Gupta M, Kocgozlu L, Sarangi BR, Margadant F, Ashraf M, Ladoux B (2015) Micropillar substrates: a tool for studying cell mechanobiology. Methods Cell Biol 125:289–308 25640435
  20. Hamadi A, Bouali M, Dontenwill M, Stoeckel H, Takeda K, Ronde P (2005) Regulation of focal adhesion dynamics and disassembly by phosphorylation of FAK at tyrosine 397. J Cell Sci 118:4415–4425 16159962 · DOI
  21. Helfman DM, Levy ET, Berthier C, Shtutman M, Riveline D, Grosheva I, Lachish-Zalait A, Elbaum M, Bershadsky AD (1999) Caldesmon inhibits nonmuscle cell contractility and interferes with the formation of focal adhesions. Mol Biol Cell 10:3097–3112 10512853 PMC25564 · DOI
  22. Juanes MA, Bouguenina H, Eskin JA, Jaiswal R, Badache A, Goode BL (2017) Adenomatous polyposis coli nucleates actin assembly to drive cell migration and microtubule-induced focal adhesion turnover. J Cell Biol 216:2859–2875 28663347 PMC5584174 · DOI
  23. Juanes MA, Fees CP, Hoeprich GJ, Jaiswal R, Goode BL (2020) EB1 directly regulates APC-mediated actin nucleation. Curr Biol 30:4763–4772.e4768 33007249 PMC7726095 · DOI
  24. Juanes MA, Isnardon D, Badache A, Brasselet S, Mavrakis M, Goode BL (2019) The role of APC-mediated actin assembly in microtubule capture and focal adhesion turnover. J Cell Biol 218:3415–3435 31471457 PMC6781439 · DOI
  25. Kenific CM, Stehbens SJ, Goldsmith J, Leidal AM, Faure N, Ye J, Wittmann T, Debnath J (2016) NBR1 enables autophagy-dependent focal adhesion turnover. J Cell Biol 212:577–590 26903539 PMC4772495 · DOI
  26. Kiosses WB, Daniels RH, Otey C, Bokoch GM, Schwartz MA (1999) A role for p21-activated kinase in endothelial cell migration. J Cell Biol 147:831–844 10562284 PMC2156168 · DOI
  27. Krylyshkina O, Kaverina I, Kranewitter W, Steffen W, Alonso MC, Cross RA, Small JV (2002) Modulation of substrate adhesion dynamics via microtubule targeting requires kinesin-1. J Cell Biol 156:349–359 11807097 PMC2199234 · DOI
  28. Lansbergen G, Grigoriev I, Mimori-Kiyosue Y, Ohtsuka T, Higa S, Kitajima I, Demmers J, Galjart N, Houtsmuller AB, Grosveld F et al (2006) CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta. Dev Cell 11:21–32 16824950 · DOI
  29. Lavelin I, Wolfenson H, Patla I, Henis YI, Medalia O, Volberg T, Livne A, Kam Z, Geiger B (2013) Differential effect of actomyosin relaxation on the dynamic properties of focal adhesion proteins. PLoS ONE 8:e73549 24039980 PMC3767655 · DOI
  30. Liu BP, Chrzanowska-Wodnicka M, Burridge K (1998) Microtubule depolymerization induces stress fibers, focal adhesions, and DNA synthesis via the GTP-binding protein Rho. Cell Adhes Commun 5:249–255 9762466 · DOI
  31. Lukinavicius G, Reymond L, D’Este E, Masharina A, Gottfert F, Ta H, Guther A, Fournier M, Rizzo S, Waldmann H et al (2014) Fluorogenic probes for live-cell imaging of the cytoskeleton. Nat Methods 11:731–733 24859753 · DOI
  32. Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10:839–850 16740485 · DOI
  33. Matov A, Applegate K, Kumar P, Thoma C, Krek W, Danuser G, Wittmann T (2010) Analysis of microtubule dynamic instability using a plus-end growth marker. Nat Methods 7:761–768 20729842 PMC3032800 · DOI
  34. Maurer SP, Fourniol FJ, Bohner G, Moores CA, Surrey T (2012) EBs recognize a nucleotide-dependent structural cap at growing microtubule ends. Cell 149:371–382 22500803 PMC3368265 · DOI
  35. Meiring JCM, Shneyer BI, Akhmanova A (2020) Generation and regulation of microtubule network asymmetry to drive cell polarity. Curr Opin Cell Biol 62:86–95 31739264 · DOI
  36. Noordstra I, Akhmanova A (2017) Linking cortical microtubule attachment and exocytosis. F1000Res 6:469 28491287 PMC5399970 · DOI
  37. Noordstra I, van den Berg CM, Boot FWJ, Katrukha EA, Yu KL, Tas RP, Portegies S, Viergever BJ, de Graaff E, Hoogenraad CC et al (2022) Organization and dynamics of the cortical complexes controlling insulin secretion in beta-cells. J Cell Sci 135:jcs259430 35006275 PMC8918791 · DOI
  38. Ong CC, Gierke S, Pitt C, Sagolla M, Cheng CK, Zhou W, Jubb AM, Strickland L, Schmidt M, Duron SG et al (2015) Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents. Breast Cancer Res 17:59 25902869 PMC4445529 · DOI
  39. Pan M, Chew TW, Wong DCP, Xiao J, Ong HT, Chin JFL, Low BC (2020) BNIP-2 retards breast cancer cell migration by coupling microtubule-mediated GEF-H1 and RhoA activation. Sci Adv 6:eaaz1534 32789168 PMC7399486 · DOI
  40. Rafiq NBM, Nishimura Y, Plotnikov SV, Thiagarajan V, Zhang Z, Shi S, Natarajan M, Viasnoff V, Kanchanawong P, Jones GE et al (2019) A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions. Nature Materials 18:638–649 31114072 · DOI
  41. Randall TS, Yip YY, Wallock-Richards DJ, Pfisterer K, Sanger A, Ficek W, Steiner RA, Beavil AJ, Parsons M, Dodding MP (2017) A small-molecule activator of kinesin-1 drives remodeling of the microtubule network. Proc Natl Acad Sci USA 114:13738–13743 29229862 PMC5748212 · DOI
  42. Ren XD, Kiosses WB, Schwartz MA (1999) Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J 18:578–585 9927417 PMC1171150 · DOI
  43. Rid R, Schiefermeier N, Grigoriev I, Small JV, Kaverina I (2005) The last but not the least: the origin and significance of trailing adhesions in fibroblastic cells. Cell Motil Cytoskeleton 61:161–171 15909298 · DOI
  44. Riveline D, Zamir E, Balaban NQ, Schwarz US, Ishizaki T, Narumiya S, Kam Z, Geiger B, Bershadsky AD (2001) Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J Cell Biol 153:1175–1186 11402062 PMC2192034 · DOI
  45. Ruane PT, Gumy LF, Bola B, Anderson B, Wozniak MJ, Hoogenraad CC, Allan VJ (2016) Tumour Suppressor Adenomatous Polyposis Coli (APC) localisation is regulated by both Kinesin-1 and Kinesin-2. Sci Rep 6:27456 27272132 PMC4895226 · DOI
  46. Schmitt MS, Colen J, Sala S, Devany J, Seetharaman S, Caillier A, Gardel ML, Oakes PW, Vitelli V (2024) Machine learning interpretable models of cell mechanics from protein images. Cell 187:481–494.e424 38194965 PMC11225795 · DOI
  47. Schober M, Raghavan S, Nikolova M, Polak L, Pasolli HA, Beggs HE, Reichardt LF, Fuchs E (2007) Focal adhesion kinase modulates tension signaling to control actin and focal adhesion dynamics. J Cell Biol 176:667–680 17325207 PMC2064024 · DOI
  48. Seetharaman S, Vianay B, Roca V, Farrugia AJ, De Pascalis C, Boeda B, Dingli F, Loew D, Vassilopoulos S, Bershadsky A et al (2022) Microtubules tune mechanosensitive cell responses. Nat Mater 21:366–377 34663953 · DOI · Paper page
  49. Shemesh T, Geiger B, Bershadsky AD, Kozlov MM (2005) Focal adhesions as mechanosensors: a physical mechanism. Proc Natl Acad Sci USA 102:12383–12388 16113084 PMC1194898 · DOI
  50. Small JV, Geiger B, Kaverina I, Bershadsky A (2002) How do microtubules guide migrating cells? Nat Rev Mol Cell Biol 3:957–964 12461561 · DOI
  51. Stehbens SJ, Paszek M, Pemble H, Ettinger A, Gierke S, Wittmann T (2014) CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover. Nat Cell Biol 16:561–573 24859005 PMC4108447 · DOI
  52. Sun Z, Tseng H-Y, Tan S, Senger F, Kurzawa L, Dedden D, Mizuno N, Wasik AA, Thery M, Dunn AR et al (2016) Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation. Nature Cell Biol 18:941–953 27548916 PMC6053543 · DOI
  53. van der Vaart B, van Riel WE, Doodhi H, Kevenaar JT, Katrukha EA, Gumy L, Bouchet BP, Grigoriev I, Spangler SA, Yu KL et al (2013) CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor. Dev Cell 27:145–160 24120883 · DOI
  54. Vicente-Manzanares M, Zareno J, Whitmore L, Choi CK, Horwitz AF (2007) Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells. J Cell Biol 176:573–580 17312025 PMC2064016 · DOI
  55. Vignaud T, Ennomani H, Thery M (2014) Polyacrylamide hydrogel micropatterning. Methods Cell Biol 120:93–116 24484659 · DOI
  56. Wu Y, Zhang K, Seong J, Fan J, Chien S, Wang Y, Lu S (2016) In-situ coupling between kinase activities and protein dynamics within single focal adhesions. Sci Rep 6:29377 27383747 PMC4935953 · DOI
  57. Yang C, Wu J, de Heus C, Grigoriev I, Liv N, Yao Y, Smal I, Meijering E, Klumperman J, Qi RZ et al (2017) EB1 and EB3 regulate microtubule minus end organization and Golgi morphology. J Cell Biol 216:3179–3198 28814570 PMC5626540 · DOI
  58. Yue J, Xie M, Gou X, Lee P, Schneider MD, Wu X (2014) Microtubules regulate focal adhesion dynamics through MAP4K4. Dev Cell 31:572–585 25490267 PMC4261153 · DOI
  59. Zheng Y, Han MKL, Zhao R, Blass J, Zhang J, Zhou DW, Colard-Itte JR, Dattler D, Colak A, Hoth M et al (2021) Optoregulated force application to cellular receptors using molecular motors. Nat Commun 12:3580 34117256 PMC8196032 · DOI

Cited by

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Authors
Aureille, J., Prabhu, S. S., Barnett, S. F., Farrugia, A. J., Arnal, I., Lafanechère, L., Low, B. C., Kanchanawong, P., Mogilner, A., & Bershadsky, A. D.
Affiliations
  • National University of Singapore (SG)
  • Inserm (FR)
  • New York University (US)
Corresponding author
  • Aureille, Julien
  • Bershadsky, Alexander D
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2024-05-20
Volume
43
Issue
13
Pages
2715-2732
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/s44318-024-00114-4
PMC
PMC11217342
OpenAlex
W4398135220
Cited by
32
References
1
Citations by year
2026: 18 · 2025: 11 · 2024: 3
FWCI
6.77
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
Funders
  • Ministry of Education - Singapore (MOE2018-T2-2-138, MOE2019-T2-1-099, MOE2019-T2-02-014, MOE2016-T3-1-002, MOET32021-0003)
  • Prime Minister‖s Office Singapore (R-714-006-006-271)
  • Fondation Neurodis (R2311CC)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Keywords
focal adhesions, microtubules, focal adhesion turnover, KANK1, talin, focal adhesion disassembly, traction force, myosin II, GEF-H1, RhoA, rocks, PAK, focal adhesion kinase, kinesin-1, APC, cell contractility, mathematical model, cell polarity, cell migration
MeSH terms
Animals, Cytoskeletal Proteins, Humans, Microtubules, Kinesins, Talin, Focal Adhesions, Myosin Type II, Adaptor Proteins, Signal Transducing, Rho Guanine Nucleotide Exchange Factors

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