Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas.: Activating STAT3 mutations in hepatocellular adenoma

Abstract : Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6-induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6-STAT3 pathway in benign hepatocellular tumorigenesis.
Type de document :
Article dans une revue
Journal of Experimental Medicine, Rockefeller University Press, 2011, 208 (7), pp.1359-66. 〈10.1084/jem.20110283〉
Liste complète des métadonnées

Littérature citée [28 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-00719918
Contributeur : Jessica Zucman-Rossi <>
Soumis le : dimanche 22 juillet 2012 - 19:37:01
Dernière modification le : lundi 29 mai 2017 - 15:34:52
Document(s) archivé(s) le : mardi 23 octobre 2012 - 02:26:46

Fichiers

Pilati_revised_texte_only.pdf
Fichiers produits par l'(les) auteur(s)

Identifiants

Collections

Citation

Camilla Pilati, Mohamed Amessou, Michel Bihl, Charles Balabaud, Jeanne Tran Van Nhieu, et al.. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas.: Activating STAT3 mutations in hepatocellular adenoma. Journal of Experimental Medicine, Rockefeller University Press, 2011, 208 (7), pp.1359-66. 〈10.1084/jem.20110283〉. 〈inserm-00719918〉

Partager

Métriques

Consultations de la notice

298

Téléchargements de fichiers

466