Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT)

signaling pathway

• JAK- Family of cytoplasmic non-receptor tyrosine kinases which get activated after the binding of a cytokine to the cell-surface cytokine receptor.

• STAT- Family of transcription factors that become activated when one of the tyrosine residues is phosphorylated by JAK.

• STAT3 dimers then translocate from the cytoplasm into the nucleus – bind to Interferon-stimulated Response Elements.

• Cellular responses to dozens of cytokines and growth factors are mediated by the evolutionarily conserved.

• Ex: Involved in Ig class switching in B Cells following a response to IL-4 which phosphorylates STAT6.

• Resistance to viral infection by interferons mediated through STAT1.

• Trans-phosphorylated JAKs then phosphorylate downstream substrates, including both the receptor and the STATs.

• Activated STATs enter the nucleus and bind as dimers or as more complex oligomers to specific enhancer sequences in target genes, thus regulating their transcription.

The JAK/STAT pathway

Harrison D A Cold Spring Harb Perspect Biol 2012;4:a011205

©2012 by Cold Spring Harbor Laboratory Press

• Responses include proliferation, differentiation, migration, apoptosis, and cell survival.

• Essential for numerous developmental and homeostatic processes, including hematopoiesis, immune cell development, stem cell maintenance, organismal growth, and mammary gland development.

• Human JAK mutations cause numerous diseases, including SCID, hyper IgE syndrome, certain leukemias, polycythemia vera, and other myeloproliferative disorders.

• Small molecular weight cell membrane-permeable drugs that target this pathways have been developed for leukemia therapy. (JAK Inhibitors)