Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains

• DOI: 10.1073/pnas.1303640110
• Publication Date: 2013-08-27T02:24:39Z
• Authors: Fern Sha; Emel Basak Gencer; Sandrine Georgeon; Akiko Koide; Norihisa Yasui; Shohei Koide; Oliver Hantschel
• Keywords: Models, Molecular; tyrosine phosphatase; 0303 health sciences; Fusion Proteins, bcr-abl; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Crystallography, X-Ray; src Homology Domains; engineered proteins; 03 medical and health sciences; Cell Transformation, Neoplastic; HEK293 Cells; Peptide Library; Humans; Protein Interaction Domains and Motifs; Amino Acid Sequence; Enzyme Inhibitors; K562 Cells; Peptides; protein interaction inhibitor; interaction proteomics; Adaptor Proteins, Signal Transducing; Protein Binding; Signal Transduction

Significance Protein–protein interactions are essential for cellular regulation, but how changes in individual interactions influence cellular physiology or cause disease remains poorly characterized. Although selective and potent inhibitors of protein–protein interactions are powerful tools, developing such reagents is challenging. This is because signaling networks are composed of members of highly conserved protein domain families, with the Src-homology 2 (SH2) domain as an archetype. To address this challenge, we used protein design to successfully generate a set of reagents, termed monobodies, directed to the SH2 domains of SH2 domain-containing phosphatase 2 (SHP2), for which no specific inhibitors had been identified. These monobodies selectively and potently inhibit SHP2 function and demonstrate utility in dissecting the signaling networks of cancer cells.