Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

This review summarises some of the knowledge we have about Crk and Grb2 family adaptor protein signalling in health and disease and outlines the current status and the challenges still remaining in the development of efficient and selective inhibitors of their protein - protein interactions. It also highlights briefly some recent successes and problems of inhibitors for proteins that functionally interact with Crk and Grb2 family adaptors, as well as opportunities, which may arise from combination therapies. Grb2 and Crk family adaptors regulate signalling pathways linked to human diseases. They are mainly composed of Src homology 2 (SH2) and Src homology 3 (SH3) domains, which serve as docking sites for signalling proteins, including various receptors, cytoplasmic kinases and GTPase regulators. Considerable insight into the biological functions and mechanisms of action of small SH2/SH3 domain adaptors has been gained in the last years from experimental approaches as diverse as targeted gene disruption and structural studies at the atomic level. This has already indicated several strategies to utilise SH2 and SH3 domain interaction inhibitors in human disease therapy. Additional molecular targets for Crk and Grb2 domain interaction blockers are expected to surface as further protein-protein interactions are discovered. Examples include newly found DOCK family proteins (DOCK3, DOCK4, and DOCK5) which are known or suspected effectors of Crk proteins and the interaction of Grb2 with the cell cycle regulator p27Kip1.