| Research Abstract |
gp130 is a subunit that is common to the receptors for the interleukin-6 family cytokines. Biological responses elicited by gp130 are thought to be mediated through the three major signals : a signal dependent on phosphorylation of tyrosine 759 (possibly involves SHP2), a signal dependent on phosphorylation of YXXQ motifs and mediated through STAT3, and signal (s) independent on tyrosine phosphorylation of gp130. 1. We previously demonstrated that both the tyrosine759-mediated and the STAT3-mediated signals are required for the gp130-mediated cell proliferation. In this project, we identified Pim genes (Pim-1, 2) and c-myc as direct targets for STAT3. We found that Pim-1 and c-Myc cooperatively regulate G1-S phase cell-cycle progression and prevent apoptosis. We also found that VCP/Cdc48 is a target for the Pim-1-mediated signal and VCP/Cdc48 is involved in anti-apoptosis. 2. We previously found that Gab1 is involved in the tyrosine 759-mediated signal using cell lines. In this project, we generated Gab1 -deficient mice and found that Gab1 is required for heart, placenta, and skin development, and grow factor (EGF, PDGF, HGF)- and cytokine (gp130)-induced ERK MAP kinase activation. 3. To reveal roles of the gp130-mediated signals in vivo, we generated a series of knockin mouse lines, in which the STAT3- and/or tyrosine 759-mediated signals are disrupted, by replacing the mouse gp13O gene with human gp130 mutant cDNAs. We found that the STAT3-mediated signal is involved in IgG2a and IgG2b production and Th1-type cytokine production, and the tyrosine 759-mediated signal negatively regulates the STAT3-mediated biological responses.
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