page_title: JAK-STAT signaling pathway
section_title: Integration with other signalling pathways
hierarchical_section_title: JAK-STAT signaling pathway / Mechanism / Integration with other signalling pathways
caption_attribution_description: English: Example of integration between JAK-STAT, MAPK and PI3K signalling pathways
context_page_description: The JAK-STAT signalling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through a process called transcription. There are three key parts of JAK-STAT signalling: Janus kinases, signal transducer and activator of transcription proteins, and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.
context_section_description: JAK-STAT signalling is able to interconnect with other cell-signalling pathways, such as the PI3K/AKT/mTOR pathway. When JAKs are activated and phosphorylate tyrosine residues on receptors, proteins with SH2 domains (such as STATs) are able bind to the phosphotyrosines, and the proteins can carry out their function. Like STATs, the PI3K protein also has an SH2 domain, and therefore it is also able to bind to these phosphorylated receptors. As a result, activating the JAK-STAT pathway can also activate PI3K/AKT/mTOR signalling.
  JAK-STAT signalling can also integrate with the MAPK/ERK pathway. Firstly, a protein important for MAPK/ERK signalling, called Grb2, has an SH2 domain, and therefore it can bind to receptors phosphorylated by JAKs (in a similar way to PI3K). Grb2 then functions to allow the MAPK/ERK pathway to progress. Secondly, a protein activated by the MAPK/ERK pathway, called MAPK (mitogen-activated protein kinase), can phosphorylate STATs, which can increase gene transcription by STATs. However, although MAPK can increase transcription induced by STATs, one study indicates that phosphorylation of STAT3 by MAPK can reduce STAT3 activity.
  One example of JAK-STAT signalling integrating with other pathways is Interleukin-2 (IL-2) receptor signaling in T cells. IL-2 receptors have γ (gamma) chains, which are associated with JAK3, which then phosphorylates key tyrosines on the tail of the receptor. Phosphorylation then recruits an adaptor protein called Shc, which activates the MAPK/ERK pathway, and this facilitates gene regulation by STAT5.
caption: An example of the integration between JAK-STAT, MAPK/ERK and PI3K/AKT/mTOR signalling pathways. JAKs phosphorylate cytokine receptors which can bind a protein called Grb2. Grb2 then activates SOS proteins which stimulate MAPK signalling. MAPK can also phosphorylate STATs. Phosphorylated cytokine receptors can also be bound by PI3K, which allows activation of AKT. ERK, STATs and Akt can then interact with other proteins. The receptor is not shown as a dimer, and only one side of the receptors are shown phosphorylated for simplification
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