Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2), a ubiquitously expressed SH2 domain containing protein tyrosine phosphatase (PTP), plays a critical role in diverse cell signaling processes. SHP-2 contains two tandem SH2 domains at the N-terminus and a PTP domain at the C-terminus, with flexible polypeptide linker regions connecting the three domains. The 2.0 {acute over (Å)} X-ray crystal structure of the self-inhibited form of SHP-2 reveals the formation of an intramolecular protein-protein interface between the N-terminal SH2 (N—SH2) domain and the PTP domain. This self-interaction is characterized by the binding of a loop on the backside of the N—SH2 domain to the catalytic pocket of the phosphatase domain, thereby blocking substrate access to the catalytic site. Numerous inter-domain hydrogen bonds exist in this conformation; some of them are direct and some are bridged by water molecules.
Polypeptide ligands with phosphotyrosine (pY) residues activate SHP-2 by binding the tandem SH2 domains, which disrupts the N—SH2:PTP interface leading to exposure of the PTP catalytic site. Thus, the recognition of pY-peptides by the SH2 domains is normally coupled with the activation of SHP2 phosphatase capability. In most circumstances, SHP-2 plays an overall positive role in transducing signals initiated from growth factors/cytokines and extracellular matrix proteins. Despite extensive studies over the past decade, the signaling mechanisms of SHP-2 are still not well understood. For example, the molecular basis for the positive role of its catalytic activity in the Erk pathway remains elusive. Part of the reason for this is the lack of SHP-2 specific inhibitors that can be used as research tools to probe SHP-2 signaling.
Consistent with its overall positive role in cell signaling, genetic lesions in the SHP-2 gene (PTPN11) that cause hyperactivation of its catalytic activity have been identified in the developmental disorder Noonan syndrome and various childhood leukemias, including juvenile myelomonocytic leukemia (JMML), B cell acute lymphoblastic leukemia, and acute myeloid leukemia. Fifty percent of the patients with Noonan syndrome, 35% of JMML, and 6% of B cell-ALL cases harbor SHP-2 mutations. Moreover, activating mutations of SHP-2 have also been identified in sporadic solid tumors. The SHP-2 mutations found in these diseases are associated with changes in amino acids located at the interface formed by the N—SH2 and PTP domains in the self-inhibited SHP-2 conformation. Therefore, it is thought that these mutations cause a decrease in the affinity of the binding between the N—SH2 and PTP domains, leading to the gain of function (GOF) by allowing access to the phosphatase catalytic site on the enzyme. Remarkably, the SHP-2 mutations appear to play a causal role in the development of these diseases since SHP-2 mutations and other JMML-associated Ras or Neurofibromatosis 1 mutations are mutually exclusive. Furthermore, recent studies have shown that single SHP-2 GOF mutations are sufficient to induce cytokine hypersensitivity in hematopoietic progenitor cells and Noonan syndrome and JMML-like myeloproliferative disease in mice.