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A Cancer Mutation Promotes EphA4 Oligomerization and Signaling by Altering the Conformation of the SAM Domain.

Authors
  • Light, Taylor P1
  • Gomez-Soler, Maricel2
  • Wang, Zichen3
  • Karl, Kelly4
  • Zapata-Mercado, Elmer4
  • Gehring, Marina P2
  • Lechtenberg, Bernhard C2
  • Pogorelov, Taras V3
  • Hristova, Kalina5
  • Pasquale, Elena B6
  • 1 Department of Materials Science and Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 2 Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 3 Department of Chemistry, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science and Technology, and National Center for Supercomputing Applications, School of Chemical Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
  • 4 Program in Molecular Biophysics, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 5 Department of Materials Science and Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA; Program in Molecular Biophysics, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address: [email protected]
  • 6 Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Jun 14, 2021
Pages
100876–100876
Identifiers
DOI: 10.1016/j.jbc.2021.100876
PMID: 34139238
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The Eph receptor tyrosine kinases and their ephrin ligands regulate many physiological and pathological processes. EphA4 plays important roles in nervous system development and adult homeostasis, while aberrant EphA4 signaling has been implicated in neurodegeneration. EphA4 may also affect cancer malignancy, but the regulation and effects of EphA4 signaling in cancer are poorly understood. A correlation between decreased patient survival and high EphA4 mRNA expression in melanoma tumors that also highly express ephrinA ligands suggests that enhanced EphA4 signaling may contribute to melanoma progression. A search for EphA4 gain-of-function mutations in melanoma uncovered a mutation of the highly conserved leucine 920 in the EphA4 sterile alpha motif (SAM) domain. We found that mutation of L920 to phenylalanine (L920F) potentiates EphA4 autophosphorylation and signaling, making it the first documented EphA4 cancer mutation that increases kinase activity. Quantitative FRET and fluorescence intensity fluctuation (FIF) analyses revealed that the L920F mutation induces a switch in EphA4 oligomer size, from a dimer to a trimer. We propose this switch in oligomer size as a novel mechanism underlying EphA4-linked tumorigenesis. Molecular dynamics simulations suggest that the L920F mutation alters EphA4 SAM domain conformation, leading to the formation of EphA4 trimers that assemble through two aberrant SAM domain interfaces. Accordingly, EphA4 wild-type and the L920F mutant are affected differently by the SAM domain and are differentially regulated by ephrin ligand stimulation. The increased EphA4 activation induced by the L920F mutation, through the novel mechanism we uncovered, supports a functional role for EphA4 in promoting pathogenesis. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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