A Sos-derived peptidimer blocks the Ras signaling pathway by binding both Grb2 SH3 domains and displays antiproliferative activity
作者： DIDIER CUSSAC , MICHEL VIDAL , CORINNE LEPRINCE , WANG‐QING LIU , FABRICE CORNILLE
关键词: Chemistry 、 Cell growth 、 Antennapedia 、 Phosphorylation 、 Mitogen-activated protein kinase 、 GRB2 、 Epidermal growth factor receptor 、 Ras Signaling Pathway 、 PI3K/AKT/mTOR pathway 、 Cell biology
摘要: With the aim of interrupting growth factor-stimulated Ras signaling pathway at level Grb2–Sos interaction, a peptidimer, made two identical proline-rich sequences from Sos linked by lysine spacer, was designed using structural data Grb2 and peptide complexed with its SH3 domains. The peptidimer affinity for is 40 nM whereas that monomer 16 μM, supporting dual recognition both domains dimer. At 50 nM, blocks selectively complexation in ER 22 (CCL 39 fibroblasts overexpressing epidermal factor receptor) cellular extracts. specifically recognizes does not interact PI3K or Nck, domain-containing adaptors. modified to enter cells coupling fragment Antennapedia homeodomain. 10 conjugate inhibits interaction (100%) MAP kinase (ERK1 ERK2) phosphorylation (60%) without modifying cells....
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