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

eLife

Francisco N Barrera¹  Vanessa P Nguyen²  Katherine M Stefanski³  Kristen R Booth⁴  Soyeon Kim⁵  Adam W Smith⁵  Justin M Westerfield⁵  Daiane S Alves⁵  Bing-Cheng Wang⁵  Xiaojun Shi⁶  Steven M Abel⁶  Jennifer Morrell-Falvey⁷ 

[1] Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, United States;Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States;Pharmacology, Case Western Reserve University, Cleveland, United States;Rammelkamp Center for Research, MetroHealth Medical Center, Cleveland, United States;Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, United States;Department of Chemistry, University of Akron, Akron, United States;Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, United States;

关键词: EphA2 activation;    receptor tyrosine kinase;    membrane active peptide;    pH responsive;   

DOI  :  10.7554/eLife.36645

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown