Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores

Alberto Elosegui-Artola; Ion Andreu; Amy E.M. Beedle; Ainhoa Lezamiz; Marina Uroz; Anita J. Kosmalska; Roger Oria; Jenny Z. Kechagia; Palma Rico-Lastres; Anabel-Lise Le Roux; Catherine M. Shanahan; Xavier Trepat; Daniel Navajas; Sergi Garcia-Manyes; Pere Roca-Cusachs

doi:10.1016/j.cell.2017.10.008

Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores

Alberto Elosegui-Artola, Ion Andreu, Amy E.M. Beedle, Ainhoa Lezamiz, Marina Uroz, Anita J. Kosmalska, Roger Oria, Jenny Z. Kechagia, Palma Rico-Lastres, Anabel-Lise Le Roux, Catherine M. Shanahan, Xavier Trepat, Daniel Navajas, Sergi Garcia-Manyes, Pere Roca-Cusachs

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Abstract

YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.

Original language	English
Pages (from-to)	1397-1410.e14
Journal	Cell
Volume	171
Issue number	6
Early online date	26 Oct 2017
DOIs	https://doi.org/10.1016/j.cell.2017.10.008
Publication status	Published - 30 Nov 2017

Keywords

mechanotransduction
mechanosensing
transcription regulation
rigidity sensing
molecular mechanical stability
nuclear pores
nuclear transport
Hippo pathway
nuclear mechanics
atomic force microscopy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2017.10.008

Force triggers YAP nuclear_ELOSEGUI-ARTOLA_Accepted4Oct2017Epub26Oct2017_GREEN AAM (CC BY NC ND)Accepted author manuscript, 513 KBLicence: CC BY-NC-ND

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Elosegui-Artola, A., Andreu, I., Beedle, A. E. M., Lezamiz, A., Uroz, M., Kosmalska, A. J., Oria, R., Kechagia, J. Z., Rico-Lastres, P., Le Roux, A-L., Shanahan, C. M., Trepat, X., Navajas, D., Garcia-Manyes, S., & Roca-Cusachs, P. (2017). Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores. Cell, 171(6), 1397-1410.e14. https://doi.org/10.1016/j.cell.2017.10.008

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title = "Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores",

abstract = "YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.",

keywords = "mechanotransduction, mechanosensing, transcription regulation, rigidity sensing, molecular mechanical stability, nuclear pores, nuclear transport, Hippo pathway, nuclear mechanics, atomic force microscopy",

author = "Alberto Elosegui-Artola and Ion Andreu and Beedle, {Amy E.M.} and Ainhoa Lezamiz and Marina Uroz and Kosmalska, {Anita J.} and Roger Oria and Kechagia, {Jenny Z.} and Palma Rico-Lastres and {Le Roux}, Anabel-Lise and Shanahan, {Catherine M.} and Xavier Trepat and Daniel Navajas and Sergi Garcia-Manyes and Pere Roca-Cusachs",

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month = nov,

day = "30",

doi = "10.1016/j.cell.2017.10.008",

language = "English",

volume = "171",

pages = "1397--1410.e14",

journal = "Cell",

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Elosegui-Artola, A, Andreu, I, Beedle, AEM, Lezamiz, A, Uroz, M, Kosmalska, AJ, Oria, R, Kechagia, JZ, Rico-Lastres, P, Le Roux, A-L, Shanahan, CM, Trepat, X, Navajas, D, Garcia-Manyes, S & Roca-Cusachs, P 2017, 'Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores', Cell, vol. 171, no. 6, pp. 1397-1410.e14. https://doi.org/10.1016/j.cell.2017.10.008

TY - JOUR

T1 - Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores

AU - Elosegui-Artola, Alberto

AU - Andreu, Ion

AU - Beedle, Amy E.M.

AU - Lezamiz, Ainhoa

AU - Uroz, Marina

AU - Kosmalska, Anita J.

AU - Oria, Roger

AU - Kechagia, Jenny Z.

AU - Rico-Lastres, Palma

AU - Le Roux, Anabel-Lise

AU - Shanahan, Catherine M.

AU - Trepat, Xavier

AU - Navajas, Daniel

AU - Garcia-Manyes, Sergi

AU - Roca-Cusachs, Pere

PY - 2017/11/30

Y1 - 2017/11/30

N2 - YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.

AB - YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.

KW - mechanotransduction

KW - mechanosensing

KW - transcription regulation

KW - rigidity sensing

KW - molecular mechanical stability

KW - nuclear pores

KW - nuclear transport

KW - Hippo pathway

KW - nuclear mechanics

KW - atomic force microscopy

U2 - 10.1016/j.cell.2017.10.008

DO - 10.1016/j.cell.2017.10.008

M3 - Article

SN - 0092-8674

VL - 171

SP - 1397-1410.e14

JO - Cell

JF - Cell

IS - 6

ER -

Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores

Abstract

Keywords

UN SDGs

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