Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies

Cell Communication and Signaling

Research

Gerhard Müller-Newen¹  Anne Mohr¹  Hildegard Schmitz-Van de Leur¹  Natalie Rinis¹  Andrea Küster¹ 

[1] Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany;

关键词: Constitutively active gp130;    IHCAs;    Stat3;    Intracellular signaling;    Endocytosis;    Neutralizing antibodies;   

DOI  :  10.1186/1478-811X-12-14

 received in 2013-12-24, accepted in 2014-02-24,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundShort in-frame deletions in the second extracellular domain of the cytokine receptor gp130 are the leading cause of inflammatory hepatocellular adenomas (IHCAs). The deletions render gp130 constitutively active. In this study we investigate the intracellular signaling potential of one of the most potent constitutively active gp130 mutants (CAgp130) found in IHCAs.ResultsTrafficking and signaling of CAgp130 were studied in stably transfected cell lines that allowed the inducible expression of CAgp130 fused to fluorescent proteins such as YFP and mCherry. In contrast to the predominantly highly glycosylated gp130 wild type (WTgp130), CAgp130 is preferentially found in the less glycosylated high-mannose form. Accordingly, the mutated receptor is retained intracellularly and therefore less prominently expressed at the cell surface. CAgp130 persistently activates Stat3 despite the presence of the feedback inhibitor SOCS3 but fails to activate Erk1/2. De novo synthesized CAgp130 signals already from the ER-Golgi compartment before having reached the plasma membrane. Cell surface expressed and endocytosed CAgp130 do not significantly contribute to signaling. As a consequence, Stat3 activation through CAgp130 cannot be inhibited by neutralizing gp130 antibodies but through overexpression of a dominant-negative Stat3 mutant.ConclusionCAgp130 and WTgp130 differ significantly with respect to glycosylation, trafficking and signaling. As a consequence of intracellular signaling pharmacological inhibition of CAgp130 will not be achieved by targeting the receptor extracellularly but by compounds that act from within the cell.

【 授权许可】

Unknown   
© Rinis et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.