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

• Published in: The Journal of cell biology Vol. 221; no. 4; p. 1
• Main Authors: Cabral-Dias, Rebecca, Lucarelli, Stefanie, Zak, Karolina, Rahmani, Sadia, Judge, Gurjeet, Abousawan, John, DiGiovanni, Laura F, Vural, Dafne, Anderson, Karen E, Sugiyama, Michael G, Genc, Gizem, Hong, Wanjin, Botelho, Roberto J, Fairn, Gregory D, Kim, Peter K, Antonescu, Costin N
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04-04-2022
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptor proteins; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AKT protein; AKT1 protein; AKT2 protein; Cancer; Cell Signaling; Clathrin; Clathrin - metabolism; Coated pits; Endocytosis; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Fyn protein; Growth factors; Humans; Inositol polyphosphate 5-phosphatase; Kinases; Perturbation; Phosphorylation; Pits; Protein composition; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-fyn - genetics; Proto-Oncogene Proteins c-fyn - metabolism; Receptors; Recruitment; Signal Transduction; Signaling; Trafficking
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201808181

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.