Synthetic Alpha-Helix Blocks Cancer Signaling Pathway

RTKs such as the epidermal growth factor receptor (EGFR) are activated by extracellular ligands. Binding of epidermal growth factor (EGF) to the EGFR activates the tyrosine kinase activity of the cytoplasmic domain of the receptor. EGFR becomes phosphorylated on tyrosine residues. Docking proteins such as GRB2 (growth factor receptor-bound protein 2) contains an SH2 domain that binds to the phosphotyrosine residues of the activated receptor. GRB2 binds to the guanine nucleotide exchange factor Sos by way of the two SH3 domains of GRB2. When the GRB2-Sos complex docks to phosphorylated EGFR, Sos becomes activated. Activated Sos then promotes the removal of GDP (guanosine diphosphate) from a member of the Ras subfamily (most notably H-Ras or K-Ras). Ras can then bind GTP (guanosine triphosphate) and become active.

Investigators at New York University (NY, USA) searched for chemical compounds capable of disrupting the Sos-Ras interaction. To this end, they developed a synthetic cell-permeable amino acid alpha-helix. The shape of this helix was based on the guanine nucleotide exchange factor Sos.

Results published in the July 17, 2011, online edition of the journal Nature Chemical Biology revealed that the helix interfered with Ras-Sos interaction and downregulated Ras signaling in response to receptor tyrosine kinase activation.

The authors believe that the synthetic alpha helix may offer a lead for the creation of pharmaceuticals will block Sos-Ras interaction.

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