Fyn is recruited to specialized clathrin coated pits and regulates EGF receptor signaling

The Epidermal Growth Factor (EGF) Receptor (EGFR) is a key receptor tyrosine kinase that controls many facets of cell physiology, including proliferation, survival and migration. EGF stimulation elicits EGFR phosphorylation and/or membrane recruitment of Grb2, Gab1 and phosphatidylinositol‐3‐kinase (PI3K), resulting in production of phosphatidylinositol‐3,4,5‐trisphosphate (PIP3), leading to Akt activation. Concomitantly upon ligand binding, EGFR is simultaneously recruited to clathrin‐coated pits (CCPs), eventually leading to receptor endocytosis. We previously uncovered that perturbation of clathrin, but not of receptor endocytosis, impairs EGF‐stimulated activation of Akt signaling (Garay et al. 2015. Mol Biol Cell.26:3504–19). Moreover, we found that some key EGFR signaling intermediates such as phosphorylated Gab1 are enriched with some CCPs. We thus proposed that in addition to their function as endocytic portals, some CCPs have a direct role in controlling EGFR signaling. How CCPs and clathrin directly control the spatiotemporal properties of EGFR signaling at the plasma membrane prior to receptor endocytosis had remained poorly understood. We uncovered that perturbations of TOM1L1 (a clathrin‐binding regulator of Src‐family kinases) and the TOM1L1‐binding Src‐family kinase Fyn impaired EGF‐stimulated Akt phosphorylation, similarly to the effects of clathrin perturbations. We found that TOM1L1 and Fyn are enriched within a subset of CCPs that also contain EGFR, and that perturbation of TOM1L1 prevented Fyn recruitment to CCPs. Importantly, TOM1L1‐ or Fyn‐positive CCPs exhibit unique properties, such as distinct lifetimes, compared to other CCPs. Thus, our results indicate that a subset of CCPs is specialized by enrichment with key signaling regulators to control EGFR signaling, a phenomenon required for subsequent Akt activation. Given the importance of EGFR in driving growth and survival of certain types of cancer, obtaining a better understanding of how CCPs organize key EGFR signals in space and time within the PM may lead to the development of novel anti‐cancer treatments. Support or Funding Information Funding for this research was provided by an Operating Grant (no. 125854), a Project Grant and a New Investigator Salary 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.A., and an Ontario Graduate Scholarship to S.L. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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