title: Reactive oxygen species and epidermal growth factor are antagonistic cues controlling SHP-2 dimerization.
abstract: The SHP-2 tyrosine phosphatase plays key regulatory roles in the modulation of the cell response to growth factors and cytokines. Over the past decade, the integration of genetic, biochemical, and structural data has helped in interpreting the pathological consequences of altered SHP-2 function. Using complementary approaches, we provide evidence here that endogenous SHP-2 can dimerize through the formation of disulfide bonds that may also involve the catalytic cysteine. We show that the fraction of dimeric SHP-2 is modulated by growth factor stimulation and by the cell redox state. Comparison of the phosphatase activities of the monomeric self-inhibited and dimeric forms indicated that the latter is 3-fold less active, thus pointing to the dimerization process as an additional mechanism for controlling SHP-2 activity. Remarkably, dimers formed by different SHP-2 mutants displaying diverse biochemical properties were found to respond differently to epidermal growth factor (EGF) stimulation. Although this differential behavior cannot be rationalized mechanistically yet, these findings suggest a possible regulatory role of dimerization in SHP-2 function.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Aurelio Pio
authors.initials: AP
authors.lastname: Nardozza
authors.forename: Melania
authors.initials: M
authors.lastname: D'Orazio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Trapannone
authors.forename: Salvatore
authors.initials: S
authors.lastname: Corallino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Filomeni
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Andrea
authors.initials: A
authors.lastname: Battistoni
authors.forename: Gianni
authors.initials: G
authors.lastname: Cesareni
authors.forename: Luisa
authors.initials: L
authors.lastname: Castagnoli
mesh_terms: D019281:Dimerization; D004815:Epidermal Growth Factor / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D004815:Epidermal Growth Factor; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11