JAK/Stat Signaling

The Janus Kinase (JAK)/Signal transducers and activators of transcription (STAT) pathway is the principal signaling mechanism for a wide array of cytokines and growth factors resulting in cell proliferation, differentiation, cell migration and apoptosis. A diverse array of ligands (e.g. cytokines, interferons, growth factors) and their receptors stimulate the JAK/STATpathway.Intracellular activation occurs when ligand binding induces the dimerization of receptor subunits. Ligand-mediated receptor dimerization leads to JAK activation by transphosphorylation of proximal JAK units. The activated JAKs subsequently phosphorylate other targets, including the receptors and the STATs, which are the main substrates. The STATs are transcription factors that reside in the cytoplasm until activated. The tyrosine residue near the C terminus of STAT is phosphorylated by JAK. This results in dimerization of STAT and translocation to the nucleus. Once in the nucleus, dimerized STATs activate or repress transcription of target genes. Thus the JAK/STAT cascade provides a mechanism to translate an extracellular signal into a transcriptional response.The JAK/STAT signaling pathway interacts with other signaling pathways like the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase (MAPK) pathway. Activated JAKs can phosphorylate their associated receptors that can serve as docking sites for SH2-containing adaptor proteins like SHP-2 and SHC. These in turn recruit the GRB2 adaptor and stimulate the Ras cascade. These signaling pathways mutually activate one another- the JAK activated RTK-RAS pathway triggers MAPK which inturn activates STATs. Other cascades like the phosphoinositide 3-kinase (PI3K) pathway are also activated by JAK and interact with the JAK/STAT pathway. In addition to activators of the JAK/STAT pathway there are also negative regulators. These include the suppressors of cytokine signaling (SOCS), protein inhibitors of activated STATs (PIAS) and protein tyrosine phosphatases (PTP).This pathway highlights the important components of JAK/STAT signaling.