EPH receptor tyrosine kinases phosphorylate the PAR-3 scaffold protein to modulate downstream signaling networks.

Cell reports 2022 Jul 05

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EPH receptors (EPHRs) constitute the largest family among receptor tyrosine kinases in humans. They are mainly involved in short-range cell-cell communication events that regulate cell adhesion, migration, and boundary formation. However, the molecular mechanisms by which EPHRs control these processes are less understood. To address this, we unravel EPHR-associated complexes under native conditions using mass-spectrometry-based BioID proximity labeling. We obtain a composite proximity network from EPHA4, -B2, -B3, and -B4 that comprises 395 proteins, most of which were not previously linked to EPHRs. We examine the contribution of several BioID-identified candidates via loss-of-function in an EPHR-dependent cell-segregation assay. We find that the signaling scaffold PAR-3 is required for cell sorting and that EPHRs directly phosphorylate PAR-3. We also delineate a signaling complex involving the C-terminal SRC kinase (CSK), whose recruitment to PAR-3 is dependent on EPHR signals. Our work describes signaling networks by which EPHRs regulate cellular phenotypes. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Sara L Banerjee, Frédéric Lessard, François J M Chartier, Kévin Jacquet, Ana I Osornio-Hernandez, Valentine Teyssier, Karim Ghani, Noémie Lavoie, Josée N Lavoie, Manuel Caruso, Patrick Laprise, Sabine Elowe, Jean-Philippe Lambert, Nicolas Bisson. EPH receptor tyrosine kinases phosphorylate the PAR-3 scaffold protein to modulate downstream signaling networks. Cell reports. 2022 Jul 05;40(1):111031