SHP-1 Requires Inhibitory Co-receptors to Down-modulate B Cell Antigen Receptor-mediated Phosphorylation of Cellular Substrates

• Published in: The Journal of biological chemistry 2001-07, Vol.276 (28), p.26648-26655
• Main Authors: Adachi, Takahiro, Wienands, Jürgen, Wakabayashi, Chisato, Yakura, Hidetaka, Reth, Michael, Tsubata, Takeshi
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - metabolism; CD22 antigen; CD72 antigen; Down-Regulation; Humans; Intracellular Signaling Peptides and Proteins; Lyn protein; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - metabolism; Receptors, Antigen, B-Cell - metabolism; SHP-1 protein; Signal Transduction; Substrate Specificity; Syk protein; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M100997200

Signaling through the B cell antigen receptor (BCR) is negatively regulated by the SH2 domain-containing protein-tyrosine phosphatase SHP-1, which requires association with tyrosine-phosphorylated proteins for activation. Upon BCR ligation, SHP-1 has been shown to associate with the BCR, the cytoplasmic protein-tyrosine kinases Lyn and Syk, and the inhibitory co-receptors CD22 and CD72. How SHP-1 is activated by BCR ligation and regulates BCR signaling is, however, not fully understood. Here we demonstrate that, in the BCR-expressing myeloma line J558Lµm3, CD72 expression reduces the BCR ligation-induced phosphorylation of the BCR component Igα/Igβ and its cytoplasmic effectors Syk and SLP-65. Substrate phosphorylation was restored by expression of dominant negative mutants of SHP-1, whereas the SHP-1 mutants failed to enhance phosphorylation of the cellular substrates in the absence of CD72. This indicates that SHP-1 is efficiently activated by CD72 but not by other pathways in J558Lµm3 cells and that inhibition of SHP-1 specifically activated by CD72 reverses CD72-induced dephosphorylation of cellular substrates in these cells. Taken together, BCR-induced SHP-1 activation is likely to require inhibitory co-receptors such as CD72, and SHP-1 appears to mediate the negative regulatory effect of CD72 on BCR signaling by dephosphorylating Igα/Igβ and its downstream signaling molecules Syk and SLP-65.