Oncogenic deletion mutants of gp130 signal from intracellular compartments

Interleukin 6 and hence activation of the IL-6 receptor signalling subunit gp130 have been linked to inflammation and tumour formation. Recently, deletion mutations in gp130 have been identified in inflammatory hepatocellular adenoma. The mutations clustered around one IL-6 binding epitope and rendered gp130 constitutively active in a ligand-independent manner. Here we can show that gp130 deletion mutants, but not wildtype gp130 localise predominantly to intracellular compartments, notably the ER and early endosomes. One of the most frequent mutants gp130 Y186-Y190del (ΔYY) is retained in the ER quality control by its association with the chaperone calnexin. Furthermore, we can show that gp130 ΔYY induces downstream signalling from both, ER and endosomes and that both signals contribute to ligand-independent cell proliferation. We also demonstrate that endosomal localisation of gp130 ΔYY is crucial for full-fledged STAT3 activation. Therefore aberrant signalling from intracellular compartments might explain the tumourigenic potential of naturally occurring somatic mutations of gp130.