Perinuclear localisation of the protein-tyrosine phosphatase SHP-1 and inhibition of epidermal growth factor-stimulated STAT1/3 activation in A431 cells

The SH2 domain protein-tyrosine phosphatase SHP-1 has been shown earlier to bind to the epidermal growth factor receptor and to have the capacity for receptor dephosphorylation, New bi- and tricistronic expression vectors (pN RTIS-21 and pNRTIS-33, respectively) based on the tetracycline system were constructed and employed to generate stable cell lines with inducible expre ssion of SHP-1. Inducible overexpression of SHP-1 in A431 cells led to atte nuation of epidermal growth factor (EGF) receptor autophosphorylation and o f EGF-induced DNA binding of 'signal transducers and activators of transcri ption' (STAT) 1 and 3. SHP-1 was localized in the cytoplasm with an enrichm ent in the perinuclear compartment. Association of SHP-1 with perinuclear s tructures may form the basis for a partial cofractionation with nuclei obse rved in different types of transfected cells and also with endogenous SHP-1 in U-937 cells. Treatment of SHP-1-overexpressing A431 cells or of HaCaT h uman keratinocytes expressing SHP-1 endogenously with the Ca2+-ionophore A2 3187 resulted in partial nuclear accumulation of SHP-1. Thus, SHP-1 may int eract with substrates or regulatory proteins in perinuclear or nuclear stru ctures.