Schematic diagram of inactive and active forms of Src kinase (PTK) and Shp2 phosphatase (PTP). (A) c-Src is maintained in an inactive conformation by intramolecular interactions between phosphorylated tyrosine 527 on the C-terminal tail and the SH2 domain and between the SH3 domain and the kinase linker region. Dephosphorylation of tyrosine 527 and binding of a p-Tyr–containing peptide to the SH2 domain leads to a switch of c-Src to an open conformation with activation of the kinase function. (B) Deletion of sequences encoding for tyrosine 527 and missense mutations within the SH3 or kinase domains (schematically represented by red stars) converts the c-Src proto-oncogene to an oncogene encoding for mutant v-Src with constitutive kinase activity. (C) Shp2 is maintained in an inactive conformation by hydrophobic interactions between amino acid residues within the N-SH2 domain and the PTP domain. Binding of a p-Tyr–containing peptide to the N-SH2 domain causes Shp2 to assume an open conformation with activation of the phosphatase function. (D) Mutations within the N-SH2 or phosphatase domains cause disruption of the hydrophobic interactions resulting in constitutive activation of the phosphatase activity. The residues most commonly mutated in childhood leukemias are shown.