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Dual clathrin and adhesion signaling systems regulate growth factor receptor activation

Marco A. Alfonzo-Mendez, Kem A. Sochacki, Marie-Paule Strub, Justin W. Taraska
doi: https://doi.org/10.1101/2020.11.09.373837
Marco A. Alfonzo-Mendez
Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 50 South Drive, Building 50, Bethesda, MD 20892
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Kem A. Sochacki
Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 50 South Drive, Building 50, Bethesda, MD 20892
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Marie-Paule Strub
Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 50 South Drive, Building 50, Bethesda, MD 20892
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Justin W. Taraska
Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 50 South Drive, Building 50, Bethesda, MD 20892
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  • For correspondence: justin.taraska@nih.gov
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ABSTRACT

The crosstalk between growth factor and adhesion receptors is key for cell growth and migration. In pathological settings, these receptors are drivers of cancer. Yet, how growth and adhesion signals are spatially organized and integrated is poorly understood. Here we use quantitative fluorescence and electron microscopy to reveal a mechanism where flat clathrin lattices partition and activate growth factor signals via a coordinated response that involves crosstalk between epidermal growth factor receptor (EGFR) and the adhesion receptor β5-integrin. We show that ligand-activated EGFR, Grb2, Src, and β5-integrin are captured by clathrin coated-structures at the plasma membrane. Clathrin structures dramatically grow in response to ligand activation into large flat plaques and provide a signaling platform that link EGFR and β5-integrin through Src-mediated phosphorylation. Disrupting this EGFR/Src/β5-integrin axis prevents both clathrin plaque growth and receptor signaling. Our study reveals a reciprocal regulation of clathrin lattices and two different receptor systems to enhance cell growth factor signaling. These findings have broad implications for the control of growth factor receptors, mechanotransduction, and endocytosis.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted November 09, 2020.
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Dual clathrin and adhesion signaling systems regulate growth factor receptor activation
Marco A. Alfonzo-Mendez, Kem A. Sochacki, Marie-Paule Strub, Justin W. Taraska
bioRxiv 2020.11.09.373837; doi: https://doi.org/10.1101/2020.11.09.373837
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Dual clathrin and adhesion signaling systems regulate growth factor receptor activation
Marco A. Alfonzo-Mendez, Kem A. Sochacki, Marie-Paule Strub, Justin W. Taraska
bioRxiv 2020.11.09.373837; doi: https://doi.org/10.1101/2020.11.09.373837

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