Dissection of Signaling Cascades through gp130 In Vivo

Abstract

We generated a series of knockin mouse lines, in which the cytokine receptor gp130-dependent STAT3 and/or SHP2 signals were disrupted, by replacing the mouse gp130 gene with human gp130 mutant cDNAs. The SHP2 signal-deficient mice (gp130F759/F759 were born normal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction. In contrast, the STAT3 signal-deficient mice (gp130FXQ/FXXQ) died perinatally, like the gp130-deficient mice (gp130D/D). The gp130F759/F759 mice showed prolonged gp130-induced STAT3 activation, indicating a negative regulatory role for SHP2. Th1-type cytokine production and IgG2a and IgG2b production were increased in the gp130F759/F759 mice, while they were decreased in the gp130FXXQ/FXXQ immune system. These results indicate that the balance of positive and negative signals generated through gp130 regulates the immune responses.

Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation

“…By day 4, the overall levels of activated MAPK were reduced, and LIF treatment did not increase MAPK phosphorylation, whereas EGF was able to stimulate MAPK on all days. This result suggests that an increase in levels of MAPK by LIF are not essential in inducing a receptive state in the LE, consistent with the observation that mutated derivatives of gp130, which do not activate MAPK, have no effect on fertility (30). The reduced levels of MAPK at the time of uterine receptivity are particularly intriguing, as other studies have revealed cross-talk between the Jak-Stat and MAPK pathways.…”

“…The MAPK pathway also is activated by LIF in a variety of cell types and has an important effect in modulating Stat3 activity (28)(29)(30). Purified LE from days 3-5 was treated with either EGF or LIF to assay MAPK phosphorylation.…”

Negative Regulation of Stat3 by Activating PTPN11 Mutants Contributes to the Pathogenesis of Noonan Syndrome and Juvenile Myelomonocytic Leukemia

“…Response to GM-CSF-Previous studies have shown that ablation of Shp2 enhances Stat3 activation (33)(34)(35). To test whether Shp2 negatively regulates Stat3 activation in hematopoietic progenitors, we retrovirally transduced low density mononuclear cells with empty vector (MIEG3), WT Shp2, or Shp2E76K, one of the most common activating PTPN11 mutations observed in JMML (9, 10, 13, 36), sorted for transduced enhanced green fluorescent protein (EGFP)-expressing cells, and cultured into macrophage progenitors as previously described (27) Fig.…”

Helicobacter pylori CagA Phosphorylation Status Determines the gp130-activated SHP2/ERK and JAK/STAT Signal Transduction Pathways in Gastric Epithelial Cells

“…The IL6/gp130/STAT3 (interleukin-6/glycoprotein 130/signal transducer and activation of transcription 3) pathway has been shown to play a role in the development of gastric cancer (24,25). IL6 exerts its biological activities through the receptor subunit gp130 (26).…”

“…However, disrupting this balance in the gp130 "knock-in" mouse induced premalignant lesions, including atrophy, intestinal metaplasia, dysplasia, and ultimately gastric cancer (24). Similarly, when the IL6 cytokine family signaling pathway is disrupted, increased STAT3 signaling may favor development of gastric adenomas, whereas increased SHP2/ERK 2 signaling may lead to mucosal inflammation (25,30).…”