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Concomitant binding of Afadin to LGN and F-actin directs planar spindle orientation.

Carminati M, Gallini S, Pirovano L, Alfieri A, Bisi S, Mapelli M
Nat Struct Mol Biol 23 155-63 (2016)
Cited: 47 times
EuropePMC logo PMID: 26751642

Abstract

Polarized epithelia form by oriented cell divisions in which the mitotic spindle aligns parallel to the epithelial plane. To orient the mitotic spindle, cortical cues trigger the recruitment of NuMA-dynein-based motors, which pull on astral microtubules via the protein LGN. We demonstrate that the junctional protein Afadin is required for spindle orientation and correct epithelial morphogenesis of Caco-2 cysts. Molecularly, Afadin binds directly and concomitantly to F-actin and to LGN. We determined the crystallographic structure of human Afadin in complex with LGN and show that it resembles the LGN-NuMA complex. In mitosis, Afadin is necessary for cortical accumulation of LGN and NuMA above the spindle poles, in an F-actin-dependent manner. Collectively, our results depict Afadin as a molecular hub governing the enrichment of LGN and NuMA at the cortex. To our knowledge, Afadin is the first-described mechanical anchor between dynein and cortical F-actin.

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Reviews citing this publication (15)

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  5. Adherens Junctions: Guardians of Cortical Development. Veeraval L, O'Leary CJ, Cooper HM. Front Cell Dev Biol 8 6 (2020)
  6. Spindle positioning and its impact on vertebrate tissue architecture and cell fate. Lechler T, Mapelli M. Nat Rev Mol Cell Biol 22 691-708 (2021)
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Articles citing this publication (31)

  1. Cell division orientation is coupled to cell-cell adhesion by the E-cadherin/LGN complex. Gloerich M, Bianchini JM, Siemers KA, Cohen DJ, Nelson WJ. Nat Commun 8 13996 (2017)
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  4. Afadin cooperates with Claudin-2 to promote breast cancer metastasis. Tabariès S, McNulty A, Ouellet V, Annis MG, Dessureault M, Vinette M, Hachem Y, Lavoie B, Omeroglu A, Simon HG, Walsh LA, Kimbung S, Hedenfalk I, Siegel PM. Genes Dev 33 180-193 (2019)
  5. Elevated leptin disrupts epithelial polarity and promotes premalignant alterations in the mammary gland. Tenvooren I, Jenks MZ, Rashid H, Cook KL, Muhlemann JK, Sistrunk C, Holmes J, Wang K, Bonin K, Hodges K, Lo HW, Shaikh A, Camarillo IG, Lelièvre SA, Seewaldt V, Vidi PA. Oncogene 38 3855-3870 (2019)
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  9. LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development. Byrd KM, Lough KJ, Patel JH, Descovich CP, Curtis TA, Williams SE. Development 143 2803-2817 (2016)
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  13. Activated ezrin controls MISP levels to ensure correct NuMA polarization and spindle orientation. Kschonsak YT, Hoffmann I. J Cell Sci 131 jcs214544 (2018)
  14. Afadin controls cell polarization and mitotic spindle orientation in developing cortical radial glia. Rakotomamonjy J, Brunner M, Jüschke C, Zang K, Huang EJ, Reichardt LF, Chenn A. Neural Dev 12 7 (2017)
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  16. mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division. Bonucci M, Kuperwasser N, Barbe S, Koka V, de Villeneuve D, Zhang C, Srivastava N, Jia X, Stokes MP, Bienaimé F, Verkarre V, Lopez JB, Jaulin F, Pontoglio M, Terzi F, Delaval B, Piel M, Pende M. Nat Commun 11 3200 (2020)
  17. Loss of the canonical spindle orientation function in the Pins/LGN homolog AGS3. Saadaoui M, Konno D, Loulier K, Goiame R, Jadhav V, Mapelli M, Matsuzaki F, Morin X. EMBO Rep 18 1509-1520 (2017)
  18. Eph signaling controls mitotic spindle orientation and cell proliferation in neuroepithelial cells. Franco M, Carmena A. J Cell Biol 218 1200-1217 (2019)
  19. Interaction between Discs large and Pins/LGN/GPSM2: a comparison across species. Schiller EA, Bergstralh DT. Biol Open 10 bio058982 (2021)
  20. Promotion of row 1-specific tip complex condensates by Gpsm2-Gαi provides insights into row identity of the tallest stereocilia. Shi Y, Lin L, Wang C, Zhu J. Sci Adv 8 eabn4556 (2022)
  21. Structural and functional insight into the effect of AFF4 dimerization on activation of HIV-1 proviral transcription. Tang D, Chen C, Liao G, Liu J, Liao B, Huang Q, Chen Q, Zhao J, Jiang H, Duan J, Huang J, Wang K, Wang J, Zhou C, Chu W, Li W, Sun B, Li Z, Dai L, Fu X, Cheng W, Xue Y, Qi S. Cell Discov 6 7 (2020)
  22. Cdk1 phosphorylation negatively regulates the activity of Net1 towards RhoA during mitosis. Ulu A, Oh W, Zuo Y, Frost JA. Cell Signal 80 109926 (2021)
  23. Morphogenetic forces planar polarize LGN/Pins in the embryonic head during Drosophila gastrulation. Camuglia J, Chanet S, Martin AC. Elife 11 e78779 (2022)
  24. The Drosophila mitotic spindle orientation machinery requires activation, not just localization. Neville KE, Finegan TM, Lowe N, Bellomio PM, Na D, Bergstralh DT. EMBO Rep 24 e56074 (2023)
  25. Cortical dynein drives centrosome clustering in cells with centrosome amplification. Mercadante DL, Aaron WA, Olson SD, Manning AL. Mol Biol Cell 34 ar63 (2023)
  26. Exploring the evolution and function of Canoe's intrinsically disordered region in linking cell-cell junctions to the cytoskeleton during embryonic morphogenesis. Gurley NJ, Szymanski RA, Dowen RH, Butcher TA, Ishiyama N, Peifer M. PLoS One 18 e0289224 (2023)
  27. Modeling reveals cortical dynein-dependent fluctuations in bipolar spindle length. Mercadante DL, Manning AL, Olson SD. Biophys J 120 3192-3210 (2021)
  28. AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis. Descovich CP, Lough KJ, Jena A, Wu JJ, Yom J, Spitzer DC, Uppalapati M, Kedziora KM, Williams SE. Elife 12 e80403 (2023)
  29. Annexin A1 is a polarity cue that directs mitotic spindle orientation during mammalian epithelial morphogenesis. Fankhaenel M, Hashemi FSG, Mourao L, Lucas E, Hosawi MM, Skipp P, Morin X, Scheele CLGJ, Elias S. Nat Commun 14 151 (2023)
  30. Interplay between the plasma membrane and cell-cell adhesion maintains epithelial identity for correct polarised cell divisions. Hosawi MM, Cheng J, Fankhaenel M, Przewloka MR, Elias S. J Cell Sci 137 jcs261701 (2024)
  31. Molecular mechanism of Afadin substrate recruitment to the receptor phosphatase PTPRK via its pseudophosphatase domain. Hay IM, Mulholland KE, Lai T, Graham SC, Sharpe HJ, Deane JE. Elife 11 e79855 (2022)


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