SHP-1 ASSOCIATES WITH BOTH PLATELET-DERIVED GROWTH-FACTOR RECEPTOR AND THE P85 SUBUNIT OF PHOSPHATIDYLINOSITOL 3-KINASE

The Src homology 2 (SH2)-containing protein tyrosine phosphatase 1, SH P-1, is highly expressed in all hematopoietic cells as well as in many non-hematopoietic cells, particularly in some malignant epithelial ce ll lines. In hematopoietic cells, SHP-1 negatively regulates multiple cytokine receptor pathways. The precise function and the targets of SH P-1 in non-hematopoietic cells, however, are largely unknown. Here we demonstrate that SHP-1 associates with both the tyrosine-phosphorylate d platelet-derived growth factor (PDGF) receptor and the p85 subunit o f phosphatidylinositol 3-kinase in MCF-7 and TRMP cells. Through the u se of mutant PDGF receptors and performing peptide competition for imm unoprecipitation, it was determined that SHP-1 independently associate s with the PDGF receptor and p85 and that its N-terminal SH2 domain is directly responsible for the interactions. Overexpression of SHP-1 in TRMP cells transfected with the PDGF receptor markedly inhibited PDGF -induced c-fos promoter activation, whereas the expression of three ca talytically inactive SHP-1 mutants increased the c-fos promoter activa tion in response to PDGF stimulation. These results indicate that SHP- 1 might negatively regulate PDGF receptor-mediated signaling in these cells. Identification of the association of SHP-1 with the PDGF recept or and p85 in MCF-7 and TRMP cells furthers our understanding of the f unction of SHP-1 in non-hematopoietic cells.