mTORC1 activity is supported by spatial association with focal adhesions

Yoana Rabanal-Ruiz; Adam Byron; Alexander Wirth; Ralitsa Madsen; Lucia Sedlackova; Graeme Hewitt; Glyn Nelson; Julian Stingele; Jimi C. Wills; Tong Zhang; André Zeug; Reinhard Fässler; Bart Vanhaesebroeck; Oliver D.K. Maddocks; Evgeni Ponimaskin; Bernadette Carroll; Viktor I. Korolchuk

doi:10.1083/JCB.202004010

mTORC1 activity is supported by spatial association with focal adhesions

Yoana Rabanal-Ruiz, Adam Byron, Alexander Wirth, Ralitsa Madsen, Lucia Sedlackova, Graeme Hewitt, Glyn Nelson, Julian Stingele, Jimi C. Wills, Tong Zhang, André Zeug, Reinhard Fässler, Bart Vanhaesebroeck, Oliver D.K. Maddocks, Evgeni Ponimaskin, Bernadette Carroll^*, Viktor I. Korolchuk

^*Corresponding author for this work

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.

Original language	English
Article number	e202004010
Journal	Journal of Cell Biology
Volume	220
Issue number	5
DOIs	https://doi.org/10.1083/JCB.202004010
Publication status	Published - Feb 2021

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Rabanal-Ruiz, Y., Byron, A., Wirth, A., Madsen, R., Sedlackova, L., Hewitt, G., Nelson, G., Stingele, J., Wills, J. C., Zhang, T., Zeug, A., Fässler, R., Vanhaesebroeck, B., Maddocks, O. D. K., Ponimaskin, E., Carroll, B., & Korolchuk, V. I. (2021). mTORC1 activity is supported by spatial association with focal adhesions. Journal of Cell Biology, 220(5), Article e202004010. https://doi.org/10.1083/JCB.202004010

@article{dd87cdcff5554df9aa6a9d56044bf768,

title = "mTORC1 activity is supported by spatial association with focal adhesions",

abstract = "The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.",

author = "Yoana Rabanal-Ruiz and Adam Byron and Alexander Wirth and Ralitsa Madsen and Lucia Sedlackova and Graeme Hewitt and Glyn Nelson and Julian Stingele and Wills, {Jimi C.} and Tong Zhang and Andr{\'e} Zeug and Reinhard F{\"a}ssler and Bart Vanhaesebroeck and Maddocks, {Oliver D.K.} and Evgeni Ponimaskin and Bernadette Carroll and Korolchuk, {Viktor I.}",

note = "Funding Information: This work was funded by the Biotechnology and Biological Sciences Research Council (V.I. Korolchuk). O.D.K. Maddocks is funded by a Cancer Research UK Career Development Fellowship (C53309/A19702). A. Byron was funded by Cancer Research UK. J. Stingele is supported by the European Research Council (starting grant 801750 DNAProteinCrosslinks) and the Alfried Krupp von Bohlen und Halbach-Stiftung (Alfried Krupp Prize for Young University Teachers). E. Ponimaskin was funded through the Deutsche Forschungsgemeinschaft (fund PO 732) and the Lobachevsky University 5-100 academic excellence program. B. Carroll is supported by a British Skin Foundation Young Investigator Award (007/yi/17) and an Academy of Medical Sciences Springboard Award (SBF005\1130). This research was funded in whole or in part by the Wellcome Trust (218547/Z/19/Z awarded to B. Carroll). For the purpose of open access, the authors have applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2021 Rabanal-Ruiz et al.",

year = "2021",

month = feb,

doi = "10.1083/JCB.202004010",

language = "English",

volume = "220",

journal = "Journal of Cell Biology",

issn = "0021-9525",

publisher = "Rockefeller University Press",

number = "5",

}

Rabanal-Ruiz, Y, Byron, A, Wirth, A, Madsen, R, Sedlackova, L, Hewitt, G, Nelson, G, Stingele, J, Wills, JC, Zhang, T, Zeug, A, Fässler, R, Vanhaesebroeck, B, Maddocks, ODK, Ponimaskin, E, Carroll, B & Korolchuk, VI 2021, 'mTORC1 activity is supported by spatial association with focal adhesions', Journal of Cell Biology, vol. 220, no. 5, e202004010. https://doi.org/10.1083/JCB.202004010

TY - JOUR

T1 - mTORC1 activity is supported by spatial association with focal adhesions

AU - Rabanal-Ruiz, Yoana

AU - Byron, Adam

AU - Wirth, Alexander

AU - Madsen, Ralitsa

AU - Sedlackova, Lucia

AU - Hewitt, Graeme

AU - Nelson, Glyn

AU - Stingele, Julian

AU - Wills, Jimi C.

AU - Zhang, Tong

AU - Zeug, André

AU - Fässler, Reinhard

AU - Vanhaesebroeck, Bart

AU - Maddocks, Oliver D.K.

AU - Ponimaskin, Evgeni

AU - Carroll, Bernadette

AU - Korolchuk, Viktor I.

N1 - Funding Information: This work was funded by the Biotechnology and Biological Sciences Research Council (V.I. Korolchuk). O.D.K. Maddocks is funded by a Cancer Research UK Career Development Fellowship (C53309/A19702). A. Byron was funded by Cancer Research UK. J. Stingele is supported by the European Research Council (starting grant 801750 DNAProteinCrosslinks) and the Alfried Krupp von Bohlen und Halbach-Stiftung (Alfried Krupp Prize for Young University Teachers). E. Ponimaskin was funded through the Deutsche Forschungsgemeinschaft (fund PO 732) and the Lobachevsky University 5-100 academic excellence program. B. Carroll is supported by a British Skin Foundation Young Investigator Award (007/yi/17) and an Academy of Medical Sciences Springboard Award (SBF005\1130). This research was funded in whole or in part by the Wellcome Trust (218547/Z/19/Z awarded to B. Carroll). For the purpose of open access, the authors have applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. Publisher Copyright: © 2021 Rabanal-Ruiz et al.

PY - 2021/2

Y1 - 2021/2

N2 - The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.

AB - The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.

UR - http://www.scopus.com/inward/record.url?scp=85102154873&partnerID=8YFLogxK

U2 - 10.1083/JCB.202004010

DO - 10.1083/JCB.202004010

M3 - Article

C2 - 33635313

AN - SCOPUS:85102154873

SN - 0021-9525

VL - 220

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 5

M1 - e202004010

ER -

mTORC1 activity is supported by spatial association with focal adhesions

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