Unliganded EphA3 dimerization promoted by the SAM domain.

Abstract

The erythropoietin-producing hepatocellular carcinoma A3 (EphA3) receptor tyrosine kinase (RTK) regulates morphogenesis during development and is overexpressed and mutated in a variety of cancers. EphA3 activation is believed to follow a 'seeding mechanism' model, in which ligand binding to the monomeric receptor acts as a trigger for signal-productive receptor clustering. We study EphA3 lateral interactions on the surface of live cells and we demonstrate that EphA3 forms dimers in the absence of ligand binding. We further show that these dimers are stabilized by interactions involving the EphA3 sterile α-motif (SAM) domain. The discovery of unliganded EphA3 dimers challenges the current understanding of the chain of EphA3 activation events and suggests that EphA3 may follow the 'pre-formed dimer' model of activation known to be relevant for other receptor tyrosine kinases. The present work also establishes a new role for the SAM domain in promoting Eph receptor lateral interactions and signalling on the cell surface.

• Authors: Deo R Singh, QingQing Cao, Christopher King, Matt Salotto, Fozia Ahmed, Xiang Yang Zhou, Elena B Pasquale, Kalina Hristova
• Journal: The Biochemical journal (Biochem J) Vol. 471 Issue 1 Pg. 101-9 (Oct 01 2015) ISSN: 1470-8728 [Electronic] England
• PMID: 26232493 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 Authors; published by Portland Press Limited.

Chemical References

• EPHA3 protein, human
• Receptor Protein-Tyrosine Kinases
• Receptor, EphA3

Topics

• Amino Acid Motifs
• HEK293 Cells
• Humans
• Protein Multimerization (physiology)
• Protein Structure, Tertiary
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)
• Receptor, EphA3
• Signal Transduction (physiology)