Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling

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

doi:10.1083/jcb.201808181

Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling

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

Medicine

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

16 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e201808181
Journal	Journal of Cell Biology
Volume	221
Issue number	4
DOIs	https://doi.org/10.1083/jcb.201808181
Publication status	Published - Apr 4 2022

Bibliographical note

Funding Information:
Funding for this research was provided by a Project Grant (PJT-156355) and a New Investigator Award from the Canadian Institutes of Health Research, as well as an Early Researcher Award (Ontario Ministry of Research, Innovation and Science) to C.N. Antonescu; an Ontario Graduate Scholarship to S. Lu-carelli, J. Abousawan, and S. Rahmani; and a Canadian Institutes of Health Research Doctoral Research Award to R. Cabral-Dias. Contributions from R.J. Botelho were funded by a Discovery Grant (RGPIN-2020-04343) from the Natural Sciences and Engineering Council of Canada, the Canada Research Chairs Program (950-232333), Ryerson University, and the Canadian Foundation for Innovation (32957). The authors declare no competing financial interests.

Publisher Copyright:
© 2022 Cabral-Dias et al.

ASJC Scopus Subject Areas

Cell Biology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1083/jcb.201808181

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Cabral-Dias, R., Lucarelli, S., Zak, K., Rahmani, S., Judge, G., Abousawan, J., Digiovanni, L. F., Vural, D., Anderson, K. E., Sugiyama, M. G., Genc, G., Hong, W., Botelho, R. J., Fairn, G. D., Kim, P. K., & Antonescu, C. N. (2022). Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling. Journal of Cell Biology, 221(4), Article e201808181. https://doi.org/10.1083/jcb.201808181

Cabral-Dias, R, Lucarelli, S, Zak, K, Rahmani, S, Judge, G, Abousawan, J, Digiovanni, LF, Vural, D, Anderson, KE, Sugiyama, MG, Genc, G, Hong, W, Botelho, RJ, Fairn, GD, Kim, PK & Antonescu, CN 2022, 'Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling', Journal of Cell Biology, vol. 221, no. 4, e201808181. https://doi.org/10.1083/jcb.201808181

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title = "Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling",

abstract = "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.",

author = "Rebecca Cabral-Dias and Stefanie Lucarelli and Karolina Zak and Sadia Rahmani and Gurjeet Judge and John Abousawan and Digiovanni, {Laura F.} and Dafne Vural and Anderson, {Karen E.} and Sugiyama, {Michael G.} and Gizem Genc and Wanjin Hong and Botelho, {Roberto J.} and Fairn, {Gregory D.} and Kim, {Peter K.} and Antonescu, {Costin N.}",

note = "Funding Information: Funding for this research was provided by a Project Grant (PJT-156355) and a New Investigator Award from the Canadian Institutes of Health Research, as well as an Early Researcher Award (Ontario Ministry of Research, Innovation and Science) to C.N. Antonescu; an Ontario Graduate Scholarship to S. Lu-carelli, J. Abousawan, and S. Rahmani; and a Canadian Institutes of Health Research Doctoral Research Award to R. Cabral-Dias. Contributions from R.J. Botelho were funded by a Discovery Grant (RGPIN-2020-04343) from the Natural Sciences and Engineering Council of Canada, the Canada Research Chairs Program (950-232333), Ryerson University, and the Canadian Foundation for Innovation (32957). The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2022 Cabral-Dias et al.",

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AU - Cabral-Dias, Rebecca

AU - Lucarelli, Stefanie

AU - Zak, Karolina

AU - Rahmani, Sadia

AU - Judge, Gurjeet

AU - Abousawan, John

AU - Digiovanni, Laura F.

AU - Vural, Dafne

AU - Anderson, Karen E.

AU - Sugiyama, Michael G.

AU - Genc, Gizem

AU - Hong, Wanjin

AU - Botelho, Roberto J.

AU - Fairn, Gregory D.

AU - Kim, Peter K.

AU - Antonescu, Costin N.

N1 - Funding Information: Funding for this research was provided by a Project Grant (PJT-156355) and a New Investigator Award from the Canadian Institutes of Health Research, as well as an Early Researcher Award (Ontario Ministry of Research, Innovation and Science) to C.N. Antonescu; an Ontario Graduate Scholarship to S. Lu-carelli, J. Abousawan, and S. Rahmani; and a Canadian Institutes of Health Research Doctoral Research Award to R. Cabral-Dias. Contributions from R.J. Botelho were funded by a Discovery Grant (RGPIN-2020-04343) from the Natural Sciences and Engineering Council of Canada, the Canada Research Chairs Program (950-232333), Ryerson University, and the Canadian Foundation for Innovation (32957). The authors declare no competing financial interests. Publisher Copyright: © 2022 Cabral-Dias et al.

PY - 2022/4/4

Y1 - 2022/4/4

N2 - 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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Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling

Abstract

Bibliographical note

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