Department of Chemistry, University of Akron, Akron, 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; Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, United States
Bing-Cheng Wang
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 Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, United States; National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, United States
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.
