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Signaling by tyrosine kinases involves direct associations between proteins with Src homology 2 (SH2) domains and sites of tyrosine phosphorylation. Specificity in signaling pathways results in part from inherent selectivity in interactions between particular SH2 domains and phosphopeptide sequences. The cytoplasmic phosphotyrosine phosphatase SH-PTP2 (Syp, PTP 1D, PTP-2C) contains two SH2 domains (N and C) which mediate its association with and activation by the platelet-derived growth factor (PDGF) and epidermal growth factor receptors and IRS-1. We have developed a competitive phosphopeptide binding assay to analyze specificity of the SH-PTP2 N-SH2 domain for phosphorylation sites of these phosphoproteins. The sequence surrounding Tyr1009 bound with greatest affinity (ID50 = 14 microM) of eight PDGF receptor-derived phosphopeptides tested. No peptides corresponding to known epidermal growth factor receptor phosphorylation sites bound with high affinity. However, an alternative sequence surrounding Tyr954 bound tightly (ID50 = 21 microM). Of the 13 IRS-1-related peptides analyzed, sequences surrounding Tyr546, Tyr895, and Tyr1172 bound with highest affinity (ID50 = 11, 4, and 1 microM, respectively). Alternative phosphopeptides generally bound with much weaker affinity (ID50 > 150 microM). These findings are consistent with recent mutational analyses of the PDGF receptor and predict site-specific interactions between SH-PTP2 and each of these phosphoproteins. Comparisons between peptide sequences suggest that the N-terminal SH2 domain of SH-PTP2 binds with highest affinity to phosphotyrosine (pY) followed by a beta-branched residue (Val, Ile, Thr) at pY+1 and a hydrophobic residue (Val, Leu, Ile) at pY+3 positions. Peptide truncation studies also indicate that residues outside of the pY-1 to pY+4 motif are required for high affinity interactions.

We have used panels of somatic cell hybrids and fluorescent in situ hybridization to determine the chromosomal localization of the novel nontransmembrane tyrosine phosphatase PTPN6 (protein tyrosine phosphatase, nonreceptor type 6), which contains two SH2 domains. PTPN6 maps to 12p13, a region commonly involved in leukemia-associated chromosomal abnormalities. Since PTPN6 is expressed at high levels in hematopoietic cells of all lineages and its expression is induced early in hematopoietic differentiation, altered expression and/or structure of PTPN6 may play a role in leukemogenesis.

The human germ-line positions of the oncogenes ABL, SIS, and FES, the cellular counterparts of the v-onc genes of Abelson murine leukemia virus, simian sarcoma virus, and feline sarcoma virus, respectively, have been determined by in situ molecular hybridization of 3H-labeled v-onc gene probes to meiotic pachytene chromosomes. The position of ABL at 9q34.1 corresponds to the breakpoint in chromosome 9 in the translocation that gives rise to the Philadelphia chromosome, t(9; 22) (q34; q11); the position of SIS at 22ql3.1 is distal to the breakpoint in this chromosome. FES at 15q26.1 is also distal to the breakpoint in chromosome 15 in the translocation commonly seen in acute promyelocytic leukemia, t(15;17) (q24;q22).

Retroviruses can be classified into two groups: those that contain oncogenes, and those that do not (for reviews, see refs. 1–5). Members of the first group (acute, or rapidly transforming retroviruses) induce neoplastic disease in infected animals within a few weeks after infection, and cause rapid transformation of target cells in tissue culture. Viruses of the second group (slowly transforming retroviruses), which lack oncogenes, induce neoplastic disease in animals only after a long latent period (4–12 months), and do not cause transformation of tissue culture cells at detectable frequency.