Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. - Archive ouverte HAL Access content directly
Journal Articles Journal of Experimental Medicine Year : 2011

Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas.

(1, 2) , (1, 2) , (1, 2) , (3) , (4) , (5) , (1, 2) , (6) , (3, 7) , (1, 2) , (1, 2) , (1, 2, 8)
1
2
3
4
5
6
7
8

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.
Fichier principal
Vignette du fichier
Pilati_revised_texte_only.pdf (710.28 Ko) Télécharger le fichier
Vignette du fichier
Binder1.pdf (3.79 Mo) Télécharger le fichier
Origin : Files produced by the author(s)
Origin : Files produced by the author(s)
Loading...

Dates and versions

inserm-00719918 , version 1 (22-07-2012)

Identifiers

Cite

Camilla Pilati, Mohamed Amessou, Michel P. 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, 2011, 208 (7), pp.1359-66. ⟨10.1084/jem.20110283⟩. ⟨inserm-00719918⟩
334 View
668 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More