Janus kinase 1 is essential for inflammatory cytokine signaling and mammary gland remodeling

Kazuhito Sakamoto, Barbara L. Wehde, Kyung Hyun Yoo, Taemook Kim, Nirakar Rajbhandari, Ha Youn Shin, Aleata A. Triplett, Patrick D. Rädler, Fabian Schuler, Andreas Villunger, Keunsoo Kang, Lothar Hennighausen, Kay Uwe Wagner

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Despite a wealth of knowledge about the significance of individual signal transducers and activators of transcription (STATs), essential functions of their upstream Janus kinases (JAKs) during postnatal development are less well defined. Using a novel mammary gland-specific JAK1 knockout model, we demonstrate here that this tyrosine kinase is essential for the activation of STAT1, STAT3, and STAT6 in the mammary epithelium. The loss of JAK1 uncouples interleukin-6-class ligands from their downstream effector, STAT3, which leads to the decreased expression of STAT3 target genes that are associated with the acutephase response, inflammation, and wound healing. Consequently, JAK1-deficient mice exhibit impaired apoptosis and a significant delay in mammary gland remodeling. Using RNA sequencing, we identified several new JAK1 target genes that are upregulated during involution. These include Bmf and Bim, which are known regulators of programmed cell death. Using a BMF/BIMdouble-knockout epithelial transplant model, we further validated that the synergistic action of these proapoptotic JAK1 targets is obligatory for the remodeling of the mammary epithelium. The collective results of this study suggest that JAK1 has nonredundant roles in the activation of particular STAT proteins and this tyrosine kinase is essential for coupling inflammatory cytokine signals to the cell death machinery in the differentiated mammary epithelium.

Original languageEnglish (US)
Pages (from-to)1673-1690
Number of pages18
JournalMolecular and cellular biology
Volume36
Issue number11
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Sakamoto, K., Wehde, B. L., Yoo, K. H., Kim, T., Rajbhandari, N., Shin, H. Y., Triplett, A. A., Rädler, P. D., Schuler, F., Villunger, A., Kang, K., Hennighausen, L., & Wagner, K. U. (2016). Janus kinase 1 is essential for inflammatory cytokine signaling and mammary gland remodeling. Molecular and cellular biology, 36(11), 1673-1690. https://doi.org/10.1128/MCB.00999-15