title: Oncogenic deletion mutants of gp130 signal from intracellular compartments.
abstract: Interleukin 6 (IL-6) and, hence, activation of the IL-6 receptor signalling subunit glycoprotein 130 (gp130; also known as interleukin-6 receptor subunit β, IL6ST), has 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 show that gp130 deletion mutants, but not wild-type gp130, localise predominantly to intracellular compartments, notably the endoplasmic reticulum (ER) and early endosomes. One of the most frequent mutants, gp130 Y186-Y190del (ΔYY) is retained in the ER quality control system because of 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 the endosomal localisation of gp130 ΔYY is crucial for fully fledged STAT3 activation. Therefore, aberrant signalling from intracellular compartments might explain the tumorigenic potential of naturally occurring somatic mutations of gp130.
authors.affiliation: Christian-Albrechts-University, Institute of Biochemistry, 24118 Kiel, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt-Arras
authors.forename: Miryam
authors.initials: M
authors.lastname: Müller
authors.forename: Marija
authors.initials: M
authors.lastname: Stevanovic
authors.forename: Silke
authors.initials: S
authors.lastname: Horn
authors.forename: Antje
authors.initials: A
authors.lastname: Schütt
authors.forename: Juri
authors.initials: J
authors.lastname: Bergmann
authors.forename: Ruven
authors.initials: R
authors.lastname: Wilkens
authors.forename: Annett
authors.initials: A
authors.lastname: Lickert
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D025461:Feedback, Physiological; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D021381:Protein Transport; D017384:Sequence Deletion / Q000235:genetics*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130
keywords: ER; Endoplasmic reticulum; Endosome; Glycoprotein 130; IHCA; IL-6; Inflammatory hepatocellular adenoma; Interleukin 6; gp130