Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 17, Pages 13743-13751Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.349167
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- Deutsche Forschungsgemeinschaft (DFG, Bonn, Germany) [SCHE 907/2-1, SFB877 A2, SFB841 C1]
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Ligand-independent constitutively active gp130 mutants were described to be responsible for the development of inflammatory hepatocellular adenomas (IHCAs). These variants had gain-of-function somatic mutations within the extracellular domain 2 (D2) of the gp130 receptor chain. Cytokine-dependent Ba/F3 cells were transduced with the constitutively active variant of gp130 featuring a deletion in the domain 2 from Tyr-186 to Tyr-190 (gp130 Delta YY). These cells showed constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and cytokine-independent proliferation. Deletion of the Ig-like domain 1 (D1) of gp130, but not anti-gp130 mAbs directed against D1, abolished constitutive activation of gp130 Delta YY, highlighting that this domain is involved in ligand-independent activation of gp130 Delta YY. Moreover, soluble variants of gp130 were not able to inhibit the constitutive activation of gp130 Delta YY. However, the inhibition of constitutive activation of gp130 Delta YY was achieved by the anti-gp130 mAb B-P4, which specifically inhibits gp130 signaling by IL-11 but not by other IL-6 type cytokines. IL-11 but not IL-6 levels were found previously to be up-regulated in IHCAs, suggesting that mutations in gp130 are leading to IL-11-like signaling. The mAb B-P4 might be a valuable tool to inhibit the constitutive activation of naturally occurring gp130 mutants in IHCAs and rare cases of gp130-associated hepatocellular carcinoma.
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