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 EGF 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 dampens receptor signaling. Our study reveals a reciprocal regulation between clathrin lattices and two different receptor systems to coordinate and enhance signaling. These findings have broad implications for the regulation of growth factor signaling, adhesion, and endocytosis.
Highlights
The crosstalk between growth factor and adhesion receptors is key for cell growth and migration
We used genome-edited HSC3 cells endogenously expressing epidermal growth factor receptor (EGFR) tagged with GFP, an established model to study EGFR endocytosis and human EGFR-dependent head and neck carcinoma[32,33,34]
There is an emerging hypothesis that flat clathrin lattices (FCLs) can act as signaling zones or adhesion sites at the plasma membrane (PM), filling unique roles outside of endocytosis
Summary
The crosstalk between growth factor and adhesion receptors is key for cell growth and migration. Clathrin structures dramatically grow in response to EGF into large flat plaques and provide a signaling platform that link EGFR and β5-integrin through Src-mediated phosphorylation. The binding of EGF to EGFR triggers receptor dimerization and cross-phosphorylation of tyrosine residues within its cytosolic domain[4] This provides docking sites for the recruitment of scaffold proteins including Grb[2], and the activation of downstream tyrosine kinases such as ERK and Src[5,6]. Using a combination of quantitative fluorescence and electron microscopy, we showed that EGF triggers large ultrastructural changes to the membrane of human squamous carcinoma (HSC3) cells These changes include the generation and dramatic expansion of large FCLs and required EGFR activation by EGF as well as Src kinase and β5-integrin. Agonist stimulation leads to persistent recruitment of EGFR, Grb[2], and β5-integrin into clathrin structures, and a corresponding loss of Src kinase
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