Signal Transduction Pathway - The JAK/STAT Pathways

The JAK/STAT pathway is one of the pathways where there is a direct connection between cell surface and nucleus. This leads to phosphorylation of transcription factor. directly by receptor-associated proteins. This is unlike the previously described - PI3-kinase and MAP-kinase pathways where there is a  cascade of proteins between cell surface and nucleus that leads to transcription factor phosphorylation. Most of the JAK/STAT pathways are expressed in white blood cells and hence the major role is in the regulation of immune system.

The JAK/STAT pathway mainly comprises of three components:

a. A Receptor - A signal from interferon, interleukin, cytokine, growth factors or chemical messenger activates the  receptor.

b. Janus Protein (JAK) - JAK have tyrosine kinase activity.

c. Signal Transducer and Activator of Transcription (STAT) - STAT proteins are transcription factors that posssess the SH2 domain.

In unstimulated cells, the STAT proteins are inactive and are localized to cytoplasm. The binding of ligand to the receptor leads to the activation of JAK. The function of JAK is activated and being a tyrosine kinase, it phosphorylates the tyrosine residues on the receptor. As a result, the sites for phosphotyrosine-binding of  SH2 domains is created. As mentioned above that STAT proteins have SH2 domains and hence these proteins are recruited to bind to phosphotyrosine residues via SH2 domain. These STATs are now phosphorylated on their tyrosine residues by JAKs. These phosphorylated tyrosine now act as a binding site for SH2 domains of other STATs. This leads to dimerization of STAT proteins. STATs can form homodimers or heterodimers. These dimers then translocates to the cell nucleus where they stimulate the activation of the target genes.

Further studies have shown that the STAT proteins may also be activated downstream of receptor tyrosine kinases where their phosphorylation may be either by the receptors themselves (for example, epidermal growth factor receptor) or by non-receptor tyrosine kinases (for example c-src).