In 2009 Rebouissou et al. reported on small in-frame somatic deletions within the IL-6ST gene encoding for gp130 in IHCAs (inflammatory hepatocellular adenoma) [1]. These mutations rendered gp130 constitutively active leading to a persistent and ligand-independent STAT3 phosphorylation and induction of the feedback inhibitor SOCS3 as well as further acute phase target genes. 

Our research focuses primarily on spatial regulation of the constitutive activity of these receptor mutants. For our investigations the most potent deletion mutant of gp130 – del(Y186-Y190), abbreviated as CAgp130 – was fluorescently labeled and stably transfected in HEK Flp-In cells that allow its inducible expression. In a first set of experiments we found major differences between the wildtype gp130 receptor and its mutant counterpart. In contrast to WTgp130 that is mainly detected in the mature form of 150 kDa CAgp130 is predominantly present in the immature 130 kDa form indicating that it is not properly processed. In line with this finding, CAgp130 is detected at the plasma membrane to a much lesser extent than WTgp130. Furthermore, both receptors show deviations in their signaling capability with CAgp130 strongly activating the Jak/STAT pathway but just partially activating the MAPK/Erk pathway. Regarding spatial regulation of signaling our investigations revealed that newly synthesized CAgp130 is able to exert its constitutive activity before reaching the plasma membrane. Surprisingly, CAgp130 localized at the plasma membrane does not significantly contribute to constitutive signaling as revealed by the use of neutralizing antibodies. Furthermore, our work provides evidence that even endocytosed CAgp130 does not exert any constitutive signaling. Constitutive signaling emanating from CAgp130 was downregulated by the transfection of dominant negative STAT3.

Our results pinpoint the ER-Golgi compartment as the main signaling platform for CAgp130 suggesting that its efficient blockade can only be achieved with compounds that act from within the cell [2].