The epidermal growth factor (EGF) receptor (EGFR) controls many aspects of cell physiology. EGF binding to EGFR elicits the membrane recruitment and activation of phosphatidylinositol-3-kinase, leading to Akt phosphorylation and activation. Concomitantly, EGFR is recruited to clathrin-coated pits (CCPs), eventually leading to receptor endocytosis. Previous work uncovered that clathrin, but not receptor endocytosis, is required for EGF-stimulated Akt activation, and that some EGFR signals are enriched in CCPs. Here, we examine how CCPs control EGFR signaling. The signaling adaptor TOM1L1 and the Src-family kinase Fyn are enriched within a subset of CCPs with unique lifetimes and protein composition. Perturbation of TOM1L1 or Fyn impairs EGF-stimulated phosphorylation of Akt2 but not Akt1. EGF stimulation also triggered the TOM1L1- and Fyn-dependent recruitment of the phosphoinositide 5-phosphatase SHIP2 to CCPs. Thus, the recruitment of TOM1L1 and Fyn to a subset of CCPs underlies a role for these structures in the support of EGFR signaling leading to Akt activation.
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4 April 2022
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March 03 2022
Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling
Rebecca Cabral-Dias,
Rebecca Cabral-Dias
*
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
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Stefanie Lucarelli,
Stefanie Lucarelli
*
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
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Karolina Zak
,
Karolina Zak
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
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Sadia Rahmani,
Sadia Rahmani
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
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Gurjeet Judge,
Gurjeet Judge
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
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John Abousawan,
John Abousawan
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
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Laura F. DiGiovanni,
Laura F. DiGiovanni
3
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
4
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
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Dafne Vural,
Dafne Vural
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
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Karen E. Anderson
,
Karen E. Anderson
5
Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK
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Michael G. Sugiyama,
Michael G. Sugiyama
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
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Gizem Genc,
Gizem Genc
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
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Wanjin Hong,
Wanjin Hong
6
Institute of Molecular and Cell Biology, A*STAR, Singapore
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Roberto J. Botelho
,
Roberto J. Botelho
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
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Gregory D. Fairn
,
Gregory D. Fairn
7
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
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Peter K. Kim
,
Peter K. Kim
3
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
4
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
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Costin N. Antonescu
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
8
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Ontario, Canada
Correspondence to Costin N. Antonescu: cantonescu@ryerson.ca
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Rebecca Cabral-Dias
*
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
Stefanie Lucarelli
*
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
Karolina Zak
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
Sadia Rahmani
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
Gurjeet Judge
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
John Abousawan
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
Laura F. DiGiovanni
3
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
4
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
Dafne Vural
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
Karen E. Anderson
5
Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK
Michael G. Sugiyama
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
Gizem Genc
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
Wanjin Hong
6
Institute of Molecular and Cell Biology, A*STAR, Singapore
Roberto J. Botelho
1
Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
2
Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario, Canada
Gregory D. Fairn
7
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
Peter K. Kim
3
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
4
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
Correspondence to Costin N. Antonescu: cantonescu@ryerson.ca
*
R. Cabral-Dias and S. Lucarelli contributed equally to this paper.
Received:
August 31 2018
Revision Received:
December 15 2021
Accepted:
January 24 2022
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
Canadian Institutes of Health Research
- Award Id(s): PJT-156355
Funder(s):
Ontario Ministry of Research, Innovation and Science
Funder(s):
Ontario Graduate Scholarship
Funder(s):
Canadian Institutes of Health Research Doctoral Research Award
Funder(s):
Natural Sciences and Engineering Council of Canada
- Award Id(s): RGPIN-2020-04343
Funder(s):
Canada Research Chairs
- Award Id(s): 950-232333
Funder(s):
Ryerson University
Funder(s):
Canadian Foundation for Innovation
- Award Id(s): 32957
© 2022 Cabral-Dias 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 (4): e201808181.
Article history
Received:
August 31 2018
Revision Received:
December 15 2021
Accepted:
January 24 2022
Connected Content
Citation
Rebecca Cabral-Dias, Stefanie Lucarelli, Karolina Zak, Sadia Rahmani, Gurjeet Judge, John Abousawan, Laura F. DiGiovanni, Dafne Vural, Karen E. Anderson, Michael G. Sugiyama, Gizem Genc, Wanjin Hong, Roberto J. Botelho, Gregory D. Fairn, Peter K. Kim, Costin N. Antonescu; Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling. J Cell Biol 4 April 2022; 221 (4): e201808181. doi: https://doi.org/10.1083/jcb.201808181
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