Co-clustering of EphB6 and ephrinB1 in trans restrains cancer cell invasion

Liang, LY; Geoghegan, ND; Mlodzianoski, M; Leis, A; Whitehead, LW; Surudoi, MG; Young, SN; Janes, P; Shepherd, D; Ghosal, D; Rogers, KL; Murphy, JM; Lucet, IS

Author(s): Liang, LY; Geoghegan, ND; Mlodzianoski, M; Leis, A; Whitehead, LW; Surudoi, MG; Young, SN; Janes, P; Shepherd, D; Ghosal, D; Rogers, KL; Murphy, JM; Lucet, IS;
Details: Publication Year 2024-04-16,Volume 7,Issue #1,Page 461
Journal Title: Communications Biology
Publication Type: Apr 16 epub ahead of print
Abstract: EphB6 is an understudied ephrin receptor tyrosine pseudokinase that is downregulated in multiple types of metastatic cancers. Unlike its kinase-active counterparts which autophosphorylate and transmit signals upon intercellular interaction, little is known about how EphB6 functions in the absence of intrinsic kinase activity. Here, we unveil a molecular mechanism of cell-cell interaction driven by EphB6. We identify ephrinB1 as a cognate ligand of EphB6 and show that in trans interaction of EphB6 with ephrinB1 on neighboring cells leads to the formation of large co-clusters at the plasma membrane. These co-clusters exhibit a decreased propensity towards endocytosis, suggesting a unique characteristic for this type of cell-cell interaction. Using lattice light-sheet microscopy, 3D structured illumination microscopy and cryo-electron tomography techniques, we show that co-clustering of EphB6 and ephrinB1 promotes the formation of double-membrane tubular structures between cells. Importantly, we also demonstrate that these intercellular structures stabilize cell-cell adhesion, leading to a reduction in the invasive behavior of cancer cells. Our findings rationalize a role for EphB6 pseudokinase as a tumor suppressor when interacting with its ligands in trans.
Publisher: Springer Nature
Research Division(s): Inflammation; Structural Biology; Advanced Technology And Biology
PubMed ID: 38627519
Publisher's Version: https://doi.org/10.1038/s42003-024-06118-4
Open Access at Publisher's Site: https://doi.org/10.1038/s42003-024-06118
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-04-18 09:15:16

Last Modified: 2024-04-18 09:22:38