A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration.

ELife
Daiane S AlvesFrancisco N Barrera

Abstract

Misregulation of the signaling axis formed by the receptor tyrosine kinase (RTK) EphA2 and its ligand, ephrinA1, causes aberrant cell-cell contacts that contribute to metastasis. Solid tumors are characterized by an acidic extracellular medium. We intend to take advantage of this tumor feature to design new molecules that specifically target tumors. We created a novel pH-dependent transmembrane peptide, TYPE7, by altering the sequence of the transmembrane domain of EphA2. TYPE7 is highly soluble and interacts with the surface of lipid membranes at neutral pH, while acidity triggers transmembrane insertion. TYPE7 binds to endogenous EphA2 and reduces Akt phosphorylation and cell migration as effectively as ephrinA1. Interestingly, we found large differences in juxtamembrane tyrosine phosphorylation and the extent of EphA2 clustering when comparing TYPE7 with activation by ephrinA1. This work shows that it is possible to design new pH-triggered membrane peptides to activate RTK and gain insights on its activation mechanism.

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Citations

Dec 28, 2019·The Journal of Biological Chemistry·Justin M Westerfield, Francisco N Barrera
Jun 5, 2020·Pharmaceuticals·Robert M Hughes, Jitka A I Virag
Jul 8, 2020·Pharmaceuticals·Sarah BaudetXavier Nicol
Dec 6, 2020·The Journal of Biological Chemistry·Katherine M StefanskiFrancisco N Barrera
Nov 7, 2019·Journal of Molecular Biology·Victor Vasquez-MontesAlexey S Ladokhin
Jan 20, 2021·The Journal of Biological Chemistry·Katherine M StefanskiFrancisco N Barrera
Nov 10, 2020·Methods : a Companion to Methods in Enzymology·K G SchaeferG M King
Jul 7, 2021·Journal of Molecular Biology·Justin M WesterfieldFrancisco N Barrera
Aug 5, 2021·Biochemical Society Transactions·Alyssa E WardFrancisco N Barrera
Aug 18, 2021·World Journal of Surgical Oncology·Yongqiang ZhangHai Ren
Aug 28, 2021·International Journal of Molecular Sciences·Amita R Sahoo, Matthias Buck
Sep 23, 2021·Faraday Discussions·Katherine G SchaeferFrancisco N Barrera
Oct 26, 2021·Faraday Discussions·Huong T KratochvilWilliam F DeGrado

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Methods Mentioned

BETA
circular dichroism
solubility studies
confocal microscopy
immunoprecipitation
pHLIP
super-resolution
Structured Illumination Microscopy
FCS
fluorescence correlation spectroscopy
myristoylation

Software Mentioned

ImageJ
SPSS
Origin
OriginLab
SPSS Statistics
Zen2 blue edition
Excel
FlexAnalysis

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