Abstract
The lipid phosphatase Ship2 represents a drug discovery target for the treatment of different diseases, including cancer. Its C-terminal sterile alpha motif domain (Ship2-Sam) associates with the Sam domain from the EphA2 receptor (EphA2-Sam). This interaction is expected to mainly induce pro-oncogenic effects in cells therefore, inhibition of the Ship2-Sam/EphA2-Sam complex may represent an innovative route to discover anti-cancer therapeutics. In the present work, we designed and analyzed several peptide sequences encompassing the interaction interface of EphA2-Sam for Ship2-Sam. Peptide conformational analyses and interaction assays with Ship2-Sam conducted through diverse techniques (CD, NMR, SPR and MST), identified a positively charged penta-amino acid native motif in EphA2-Sam, that once repeated three times in tandem, binds Ship2-Sam. NMR experiments show that the peptide targets the negatively charged binding site of Ship2-Sam for EphA2-Sam. Preliminary in vitro cell-based assays indicate that -at 50 µM concentration- it induces necrosis of PC-3 prostate cancer cells with more cytotoxic effect on cancer cells than on normal dermal fibroblasts. This work represents a pioneering study that opens further opportunities for the development of inhibitors of the Ship2-Sam/EphA2-Sam complex for therapeutic applications.
Highlights
The lipid phosphatase Ship[2] represents a drug discovery target for the treatment of different diseases, including cancer
Ship[2] is an inhibitor of EphA2 receptor endocytosis[9]; EphA2 is a tyrosine kinase receptor that plays a complex role in cancer and is a known target in anticancer drug discovery[10]
Targeting the Ship2-sterile alpha-motif (Sam)/EphA2-Sam complex with peptide antagonists may represent an alternative approach for the discovery of anticancer therapeutics
Summary
The lipid phosphatase Ship[2] represents a drug discovery target for the treatment of different diseases, including cancer. Ship[2] (phosphatidylinositol 3,4,5-triphosphate 5-phosphatase 2) catalyses the dephosphorylation of PIP3 in position 5 to generate phosphatidylinositol (3, 4) P2 and downregulates different processes that are activated by PI3K (Phosphatidyl-Inositol 3 Kinase)[1,2]. In addition to this enzymatic activity, a prominent feature of Ship[2] is the presence within its primary sequence of several regions able to mediate protein-protein interactions. Ship[2] is an inhibitor of EphA2 receptor endocytosis[9]; EphA2 is a tyrosine kinase receptor that plays a complex role in cancer and is a known target in anticancer drug discovery[10]
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