PREreviews of Decoding EGFR ligand bias through an endocytic organelle platform

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Decoding EGFR ligand bias through an endocytic organelle platform

by Gorana Jendrisek, Deborah Mesa, Stefano Freddi, Giorgia Miloro, Chiara Tordonato, Andrea Francesco Benvenuto, Micaela Quarto, Margherita Caputo, Andrea Raimondi, Giusi Caldieri, Elisa Barbieri, Simone Pelicci, Mario Faretta, Maria Grazia Malabarba, Diego Chianese, Francesca Begnozzi, Paolo Pinton, Massimo Bonora, Pier Paolo Di Fiore, and Sara Sigismund

Posted: August 4, 2026
Server: bioRxiv
DOI: 10.64898/2026.08.03.742496

Abstract

How growth factor receptors decode ligand identity into distinct cellular responses remains a fundamental question in cell signaling. Here, we identify a receptor-proximal mechanism that links ligand-specific EGFR activation to distinct endocytic and biological outputs. We show that EGF, but not TGFα, selectively engages a RAC1-PLCγ2-IP3R signaling axis that supports EGFR non-clathrin endocytosis (NCE). PLCγ2, but not PLCγ1, localizes to RTN3-dependent PM-ER contact sites, where it generates localized Ca²⁺ signals required for completion of NCE, mitochondrial activation and cell motility. This specificity requires the RAC-binding interface of PLCγ2 and is associated with RAC1-dependent formation of CTxB-positive PM regions, indicating that spatial organization contributes to signaling specificity. TGFα fails to efficiently assemble the EGFR-associated organelle platform and instead favors clathrin-dependent EGFR uptake, prolonged proliferative signaling, greater organoid yield, and reduced migration compared with EGF. Together, our findings identify the RAC1-PLCγ2 axis as the key determinant that decodes EGFR ligand bias by coupling receptor trafficking to the metabolic program that supports cell migration.

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PREreview by Emmanuel Odame et al. of ASAPbio Cell Biology Crowd

Authored by Emmanuel Odame, Chinyere Mary-Cynthia Ikele, Ayobami Tosin Adegbenro, Grace Valentine Olagunju, Diptarup Mallick, Jumana Badar, and 2 other authors of ASAPbio Cell Biology Crowd

This manuscript investigates the cellular and molecular mechanisms driving cell migration, specifically examining spatial-temporal dynamics across a standard 24-hour assay window. By focusing on EGFR-mediated signaling downstream of key regulatory nodes, including PLCγ2, IP3R, and RTN3, the…

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