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Role of the JAK-STAT Signalling Pathway in Cancer

  1. Pranabananda Dutta,
  2. Willis X Li

Published Online: 18 OCT 2013

DOI: 10.1002/9780470015902.a0025214



How to Cite

Dutta, P. and Li, W. X. 2013. Role of the JAK-STAT Signalling Pathway in Cancer. eLS. .

Author Information

  1. University of California San Diego, La Jolla, California, USA

Publication History

  1. Published Online: 18 OCT 2013


The JAK-STAT pathway is important in cytokine-mediated immune responses. Research in the JAK/STAT field has elucidated its roles in various cellular processes such as proliferation, apoptosis and migration, and has found frequent dysregulation of the JAK/STAT pathway in diverse types of cancer. In recent years, JAK and STAT have also been implicated in a noncanonical mode of action: the regulation of genomic stability independent of their functions in cytokine signalling. Research in Drosophila has shown that nuclear, unphosphorylated STAT physically interacts with heterochromatin protein 1 (HP1) and stabilises its binding to heterochromatin. A similar interaction occurs in human cells, where unphosphorylated STAT5A interacts with HP1α and acts as a tumour suppressor. Nuclear JAK2, however, functions as a histone tyrosine kinase, displacing HP1α from chromatin. These data have important implications for human cancer: They suggest new drug therapies, which could target the noncanonical functions of JAK and STAT. In this article, we discuss how the canonical arm of the JAK-STAT pathway functions in tumourigenesis, focussing on JAK and on STAT1, STAT3 and STAT5. We then discuss recent findings regarding epigenetic silencing of JAK/STAT pathway components, and the direct involvement of JAK and STAT in regulating heterochromatin integrity.

Key Concepts:

  • The tyrosine kinase JAK and its downstream target STAT respond to cytokine signalling in cells.

  • In response to cytokines, JAK itself is phosphorylated, leading to its activation. The activated JAK kinase then phosphorylates specific STATs.

  • STAT proteins dimerise and translocate into the nucleus upon phosphorylation by JAK, where they bind to DNA and regulate transcription.

  • Overactivation of the JAK-STAT pathway can cause cancer by bypassing apoptosis and cell cycle checkpoints.

  • Unphosphorylated STAT is also found in the nuclei and mitochondria of cells that are not stimulated by cytokines.

  • Mitochondrial STAT upregulates cellular respiration and can promote oncogenic transformation.

  • Unphosphorylated nuclear STAT binds to HP1α and stabilises heterochromatin. STAT5A in colon cancer cells acts as a tumour suppressor via this mechanism.

  • Nuclear JAK2 is a histone tyrosine kinase. Phosphorylation of histone 3 tyrosine 41 displaces HP1α/CBX5 from chromatin and contributes to tumourigenicity.

  • In some cancers, DNA methylation suppresses the expression of inhibitory SOCS proteins, resulting in uncontrolled JAK/STAT pathway activation.


  • JAK;
  • STAT;
  • cancer;
  • epigenetic;
  • heterochromatin;
  • metastasis;
  • angiogenesis;
  • HP1;
  • CpG methylation