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

• Published in: Cell reports (Cambridge) Vol. 40; no. 1; p. 111031
• Main Authors: Banerjee, Sara L., Lessard, Frédéric, Chartier, François J.M., Jacquet, Kévin, Osornio-Hernandez, Ana I., Teyssier, Valentine, Ghani, Karim, Lavoie, Noémie, Lavoie, Josée N., Caruso, Manuel, Laprise, Patrick, Elowe, Sabine, Lambert, Jean-Philippe, Bisson, Nicolas
• Format: Journal Article
• Language: English
• Published: Elsevier 05.07.2022
• Subjects: Cell biology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111031

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.