A WxW Motif is required for the Anticancer Activity of TAT-RasGAP317-326 [Cell Biology]

July 9th, 2014 by Barras, D., Chevalier, N., Zoete, V., Dempsey, R., Lapouge, K., Olayioye, M. A., Michielin, O., Widmann, C.

TAT-RasGAP317-326, a cell-permeable 10 amino acid long peptide derived from the N2 fragment of p120 Ras GTPase activating protein (RasGAP), sensitizes tumor cells to apoptosis induced by various anticancer therapies. This RasGAP-derived peptide, by targeting the deleted in liver cancer-1 (DLC1) tumor suppressor, also hampers cell migration and invasion by promoting cell adherence and by inhibiting cell movement. Here we systematically investigated the role of each amino acid within the RasGAP317-326 sequence for the anti-cancer activities of TAT-RasGAP317-326. We report here that the first three amino acids of this sequence, tryptophan (W) - methionine (M) - tryptophan (W), are necessary and sufficient to sensitize cancer cells to cisplatin-induced apoptosis and to reduce cell migration. The WMW motif was found to be critical for the binding of fragment N2 to DLC1. These results define the interaction mode between the active anti-cancer sequence of RasGAP and DLC1. This knowledge will facilitate the design of small molecules bearing the tumor sensitizing and anti-metastatic activities of TAT-RasGAP317-326.