---
_id: '14080'
abstract:
- lang: eng
  text: Extracellular signal-regulated kinase (ERK) has been recognized as a critical
    regulator in various physiological and pathological processes. Extensive research
    has elucidated the signaling mechanisms governing ERK activation via biochemical
    regulations with upstream molecules, particularly receptor tyrosine kinases (RTKs).
    However, recent advances have highlighted the role of mechanical forces in activating
    the RTK–ERK signaling pathways, thereby opening new avenues of research into mechanochemical
    interplay in multicellular tissues. Here, we review the force-induced ERK activation
    in cells and propose possible mechanosensing mechanisms underlying the mechanoresponsive
    ERK activation. We conclude that mechanical forces are not merely passive factors
    shaping cells and tissues but also active regulators of cellular signaling pathways
    controlling collective cell behaviors.
acknowledgement: TH was supported by JSPS KAKENHI Grant (no. 21H05290) and the Ministry
  of Education under the Research Centres of Excellence programme through the Mechanobiology
  Institute at National University of Singapore and by Department of Physiology at
  National University of Singapore. NH was supported by JSPS KAKENHI Grant (no. 20K22653).
  KA was supported by JSPS KAKENHI Grants (no. 19H05798 and no. 22H02625). MM was
  supported by JSPS KAKENHI Grants (no. 19H00993 and no. 20H05898) and JST Moonshot
  R&D Grant JPMJPS2022. We appreciate Virgile Viasnoff and the lab members for their
  valuable comments on the manuscript. We apologize to authors whose work could not
  be highlighted due to space limitations.
article_number: '102217'
article_processing_charge: Yes (in subscription journal)
article_type: review
author:
- first_name: Tsuyoshi
  full_name: Hirashima, Tsuyoshi
  last_name: Hirashima
- first_name: Naoya
  full_name: Hino, Naoya
  id: 5299a9ce-7679-11eb-a7bc-d1e62b936307
  last_name: Hino
- first_name: Kazuhiro
  full_name: Aoki, Kazuhiro
  last_name: Aoki
- first_name: Michiyuki
  full_name: Matsuda, Michiyuki
  last_name: Matsuda
citation:
  ama: Hirashima T, Hino N, Aoki K, Matsuda M. Stretching the limits of extracellular
    signal-related kinase (ERK) signaling — Cell mechanosensing to ERK activation.
    <i>Current Opinion in Cell Biology</i>. 2023;84(10). doi:<a href="https://doi.org/10.1016/j.ceb.2023.102217">10.1016/j.ceb.2023.102217</a>
  apa: Hirashima, T., Hino, N., Aoki, K., &#38; Matsuda, M. (2023). Stretching the
    limits of extracellular signal-related kinase (ERK) signaling — Cell mechanosensing
    to ERK activation. <i>Current Opinion in Cell Biology</i>. Elsevier. <a href="https://doi.org/10.1016/j.ceb.2023.102217">https://doi.org/10.1016/j.ceb.2023.102217</a>
  chicago: Hirashima, Tsuyoshi, Naoya Hino, Kazuhiro Aoki, and Michiyuki Matsuda.
    “Stretching the Limits of Extracellular Signal-Related Kinase (ERK) Signaling
    — Cell Mechanosensing to ERK Activation.” <i>Current Opinion in Cell Biology</i>.
    Elsevier, 2023. <a href="https://doi.org/10.1016/j.ceb.2023.102217">https://doi.org/10.1016/j.ceb.2023.102217</a>.
  ieee: T. Hirashima, N. Hino, K. Aoki, and M. Matsuda, “Stretching the limits of
    extracellular signal-related kinase (ERK) signaling — Cell mechanosensing to ERK
    activation,” <i>Current Opinion in Cell Biology</i>, vol. 84, no. 10. Elsevier,
    2023.
  ista: Hirashima T, Hino N, Aoki K, Matsuda M. 2023. Stretching the limits of extracellular
    signal-related kinase (ERK) signaling — Cell mechanosensing to ERK activation.
    Current Opinion in Cell Biology. 84(10), 102217.
  mla: Hirashima, Tsuyoshi, et al. “Stretching the Limits of Extracellular Signal-Related
    Kinase (ERK) Signaling — Cell Mechanosensing to ERK Activation.” <i>Current Opinion
    in Cell Biology</i>, vol. 84, no. 10, 102217, Elsevier, 2023, doi:<a href="https://doi.org/10.1016/j.ceb.2023.102217">10.1016/j.ceb.2023.102217</a>.
  short: T. Hirashima, N. Hino, K. Aoki, M. Matsuda, Current Opinion in Cell Biology
    84 (2023).
date_created: 2023-08-20T22:01:12Z
date_published: 2023-10-01T00:00:00Z
date_updated: 2024-01-30T12:52:42Z
day: '01'
ddc:
- '570'
department:
- _id: CaHe
doi: 10.1016/j.ceb.2023.102217
external_id:
  isi:
  - '001054692200001'
  pmid:
  - '37574635'
file:
- access_level: open_access
  checksum: 25923f8ae71344e8974530dd23c71bdc
  content_type: application/pdf
  creator: dernst
  date_created: 2024-01-30T12:52:12Z
  date_updated: 2024-01-30T12:52:12Z
  file_id: '14909'
  file_name: 2023_CurrentOpinionCellBio_Hirashima.pdf
  file_size: 1173762
  relation: main_file
  success: 1
file_date_updated: 2024-01-30T12:52:12Z
has_accepted_license: '1'
intvolume: '        84'
isi: 1
issue: '10'
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
pmid: 1
publication: Current Opinion in Cell Biology
publication_identifier:
  eissn:
  - 1879-0410
  issn:
  - 0955-0674
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Stretching the limits of extracellular signal-related kinase (ERK) signaling
  — Cell mechanosensing to ERK activation
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 84
year: '2023'
...
---
_id: '12238'
abstract:
- lang: eng
  text: Upon the initiation of collective cell migration, the cells at the free edge
    are specified as leader cells; however, the mechanism underlying the leader cell
    specification remains elusive. Here, we show that lamellipodial extension after
    the release from mechanical confinement causes sustained extracellular signal-regulated
    kinase (ERK) activation and underlies the leader cell specification. Live-imaging
    of Madin-Darby canine kidney (MDCK) cells and mouse epidermis through the use
    of Förster resonance energy transfer (FRET)-based biosensors showed that leader
    cells exhibit sustained ERK activation in a hepatocyte growth factor (HGF)-dependent
    manner. Meanwhile, follower cells exhibit oscillatory ERK activation waves in
    an epidermal growth factor (EGF) signaling-dependent manner. Lamellipodial extension
    at the free edge increases the cellular sensitivity to HGF. The HGF-dependent
    ERK activation, in turn, promotes lamellipodial extension, thereby forming a positive
    feedback loop between cell extension and ERK activation and specifying the cells
    at the free edge as the leader cells. Our findings show that the integration of
    physical and biochemical cues underlies the leader cell specification during collective
    cell migration.
acknowledgement: We thank the members of the Matsuda Laboratory for their helpful
  discussion and encouragement, and we thank K. Hirano and K. Takakura for their technical
  assistance. This work was supported by the Kyoto University Live Imaging Center.
  Financial support was provided in the form of JSPS KAKENHI grants (nos. 17J02107
  and 20K22653 to N.H., and 20H05898 and 19H00993 to M.M.), a JST CREST grant (no.
  JPMJCR1654 to M.M.), a Moonshot R&D grant (no. JPMJPS2022-11 to M.M.), Generalitat
  de Catalunya and the CERCA Programme (no. SGR-2017-01602 to X.T.), MICCINN/FEDER
  (no. PGC2018-099645-B-I00 to X.T.), and European Research Council (no. Adv-883739
  to X.T.). IBEC is a recipient of a Severo Ochoa Award of Excellence from the MINECO.
  This work was partly supported by an Extramural Collaborative Research Grant of
  Cancer Research Institute, Kanazawa University.
article_processing_charge: No
article_type: original
author:
- first_name: Naoya
  full_name: Hino, Naoya
  id: 5299a9ce-7679-11eb-a7bc-d1e62b936307
  last_name: Hino
- first_name: Kimiya
  full_name: Matsuda, Kimiya
  last_name: Matsuda
- first_name: Yuya
  full_name: Jikko, Yuya
  last_name: Jikko
- first_name: Gembu
  full_name: Maryu, Gembu
  last_name: Maryu
- first_name: Katsuya
  full_name: Sakai, Katsuya
  last_name: Sakai
- first_name: Ryu
  full_name: Imamura, Ryu
  last_name: Imamura
- first_name: Shinya
  full_name: Tsukiji, Shinya
  last_name: Tsukiji
- first_name: Kazuhiro
  full_name: Aoki, Kazuhiro
  last_name: Aoki
- first_name: Kenta
  full_name: Terai, Kenta
  last_name: Terai
- first_name: Tsuyoshi
  full_name: Hirashima, Tsuyoshi
  last_name: Hirashima
- first_name: Xavier
  full_name: Trepat, Xavier
  last_name: Trepat
- first_name: Michiyuki
  full_name: Matsuda, Michiyuki
  last_name: Matsuda
citation:
  ama: Hino N, Matsuda K, Jikko Y, et al. A feedback loop between lamellipodial extension
    and HGF-ERK signaling specifies leader cells during collective cell migration.
    <i>Developmental Cell</i>. 2022;57(19):2290-2304.e7. doi:<a href="https://doi.org/10.1016/j.devcel.2022.09.003">10.1016/j.devcel.2022.09.003</a>
  apa: Hino, N., Matsuda, K., Jikko, Y., Maryu, G., Sakai, K., Imamura, R., … Matsuda,
    M. (2022). A feedback loop between lamellipodial extension and HGF-ERK signaling
    specifies leader cells during collective cell migration. <i>Developmental Cell</i>.
    Elsevier. <a href="https://doi.org/10.1016/j.devcel.2022.09.003">https://doi.org/10.1016/j.devcel.2022.09.003</a>
  chicago: Hino, Naoya, Kimiya Matsuda, Yuya Jikko, Gembu Maryu, Katsuya Sakai, Ryu
    Imamura, Shinya Tsukiji, et al. “A Feedback Loop between Lamellipodial Extension
    and HGF-ERK Signaling Specifies Leader Cells during Collective Cell Migration.”
    <i>Developmental Cell</i>. Elsevier, 2022. <a href="https://doi.org/10.1016/j.devcel.2022.09.003">https://doi.org/10.1016/j.devcel.2022.09.003</a>.
  ieee: N. Hino <i>et al.</i>, “A feedback loop between lamellipodial extension and
    HGF-ERK signaling specifies leader cells during collective cell migration,” <i>Developmental
    Cell</i>, vol. 57, no. 19. Elsevier, p. 2290–2304.e7, 2022.
  ista: Hino N, Matsuda K, Jikko Y, Maryu G, Sakai K, Imamura R, Tsukiji S, Aoki K,
    Terai K, Hirashima T, Trepat X, Matsuda M. 2022. A feedback loop between lamellipodial
    extension and HGF-ERK signaling specifies leader cells during collective cell
    migration. Developmental Cell. 57(19), 2290–2304.e7.
  mla: Hino, Naoya, et al. “A Feedback Loop between Lamellipodial Extension and HGF-ERK
    Signaling Specifies Leader Cells during Collective Cell Migration.” <i>Developmental
    Cell</i>, vol. 57, no. 19, Elsevier, 2022, p. 2290–2304.e7, doi:<a href="https://doi.org/10.1016/j.devcel.2022.09.003">10.1016/j.devcel.2022.09.003</a>.
  short: N. Hino, K. Matsuda, Y. Jikko, G. Maryu, K. Sakai, R. Imamura, S. Tsukiji,
    K. Aoki, K. Terai, T. Hirashima, X. Trepat, M. Matsuda, Developmental Cell 57
    (2022) 2290–2304.e7.
date_created: 2023-01-16T09:51:39Z
date_published: 2022-10-01T00:00:00Z
date_updated: 2023-08-04T09:38:53Z
day: '01'
department:
- _id: CaHe
doi: 10.1016/j.devcel.2022.09.003
external_id:
  isi:
  - '000898428700006'
  pmid:
  - '36174555'
intvolume: '        57'
isi: 1
issue: '19'
keyword:
- Developmental Biology
- Cell Biology
- General Biochemistry
- Genetics and Molecular Biology
- Molecular Biology
language:
- iso: eng
month: '10'
oa_version: None
page: 2290-2304.e7
pmid: 1
publication: Developmental Cell
publication_identifier:
  issn:
  - 1534-5807
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: A feedback loop between lamellipodial extension and HGF-ERK signaling specifies
  leader cells during collective cell migration
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 57
year: '2022'
...