Integrins mediate cell adhesion by connecting the extracellular matrix to the intracellular cytoskeleton and orchestrate signal transduction in response to chemical and mechanical stimuli by interacting with many cytoplasmic proteins. We used BioID to interrogate the interactomes of β1 and β3 integrins in epithelial cells and identified PEAK1 as an interactor of the RGD-binding integrins α5β1, αVβ3, and αVβ5 in focal adhesions. We demonstrate that the interaction between integrins and PEAK1 occurs indirectly through Tensin3, requiring both the membrane-proximal NPxY motif on the integrin β tail and binding of the SH2 domain of Tensin3 to phosphorylated Tyr-635 on PEAK1. Phosphorylation of Tyr-635 is mediated by Src and regulates cell migration. Additionally, we found that Shc1 localizes in focal adhesions in a PEAK1 phosphorylated Tyr-1188–dependent fashion. Besides binding Shc1, PEAK1 also associates with a protein cluster that mediates late EGFR/Shc1 signaling. We propose a model in which PEAK1 binds Tensin3 and Shc1 to converge integrin and growth factor receptor signal transduction.
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1 August 2022
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June 10 2022
PEAK1 Y635 phosphorylation regulates cell migration through association with Tensin3 and integrins
Alba Zuidema
,
Alba Zuidema
1
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Paul Atherton
,
Paul Atherton
1
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Maaike Kreft
,
Maaike Kreft
1
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Liesbeth Hoekman
,
Liesbeth Hoekman
2
Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Onno B. Bleijerveld
,
Onno B. Bleijerveld
2
Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Nagarjuna Nagaraj,
Nagarjuna Nagaraj
3
Mass Spectrometry Core Facility at the Max-Planck Institute of Biochemistry, Planegg, Germany
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Nanpeng Chen
,
Nanpeng Chen
4
Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Planegg, Germany
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Reinhard Fässler,
Reinhard Fässler
4
Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Planegg, Germany
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Arnoud Sonnenberg
1
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Correspondence to Arnoud Sonnenberg: a.sonnenberg@nki.nl
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Alba Zuidema
1
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Paul Atherton
1
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Maaike Kreft
1
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Liesbeth Hoekman
2
Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Onno B. Bleijerveld
2
Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Nagarjuna Nagaraj
3
Mass Spectrometry Core Facility at the Max-Planck Institute of Biochemistry, Planegg, Germany
Nanpeng Chen
4
Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Planegg, Germany
Reinhard Fässler
4
Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Planegg, Germany
Correspondence to Arnoud Sonnenberg: a.sonnenberg@nki.nl
Received:
August 05 2021
Revision Received:
March 22 2022
Accepted:
May 18 2022
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
Dutch Cancer Society
- Award Id(s): project 12143
Funder(s):
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Funder(s):
Alexander von Humboldt Foundation
© 2022 Zuidema et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2022) 221 (8): e202108027.
Article history
Received:
August 05 2021
Revision Received:
March 22 2022
Accepted:
May 18 2022
Citation
Alba Zuidema, Paul Atherton, Maaike Kreft, Liesbeth Hoekman, Onno B. Bleijerveld, Nagarjuna Nagaraj, Nanpeng Chen, Reinhard Fässler, Arnoud Sonnenberg; PEAK1 Y635 phosphorylation regulates cell migration through association with Tensin3 and integrins. J Cell Biol 1 August 2022; 221 (8): e202108027. doi: https://doi.org/10.1083/jcb.202108027
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