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

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.

Hepatocyte nuclear factor 1 alpha influences pancreatic cancer growth and metastasis

“…We focused specifically on the role of HNF1α in the development and progression of PDAC in hopes to apply this knowledge in the development of more targeted and effective treatments for this disease. We found that silencing HNF1α reduced the proliferative, migratory, invasive and colony forming capabilities of pancreatic cancer cells, consistent with previous research that has identified it as a novel oncogene in pancreatic cancer 10 . Thus, continued research into the role of HNF1α is worthy of further exploration.…”

“…Further, it also been shown that HNF1α significantly promoted pancreatic cancers by influencing fibroblast growth factor receptor 4 23 . Recently, it has been shown that HNF1α is a putative regulator of PDAC stem cell gene signature 10 . Further, it has also been demonstrated that HNF1α is required for tumor growth, tumorsphere formation, invasion and migration.…”

“…In addition, the mechanism by which HNF1α promotes PDAC stemness is by regulating the pluripotency factor POU5F1/OCT4. Expression of HNF1α upregulated genes has been associated with poor survival outcomes in PDAC patients 10 .…”

“…As such, HNF1α has been suggested to play a tumor suppressing role, specifically in both liver and pancreatic cancers. However, recent studies have shown an oncogenic role for HNF1α 10 , 11 . The current knowledge on the exact role of HNF-1α in pancreatic carcinogenesis is contradictory, and the significance of targeting this protein for therapeutic purposes remains unidentified.…”

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

“…TYPE7 is a pH-sensitive peptide derived from the transmembrane domain of its target. Inducing a pH drop leads to the translocation of the peptide to the plasma membrane where it binds EphA2, promotes its oligomerization, and activates its downstream signaling [120]. A subset of peptides also targets EphA intracellular domains including the Sterile Alpha Motif (SAM) of EphA2.…”