- The JAK-STAT pathway provides a direct route for transmitting signals from cell surface receptors to the nucleus. When cytokines or growth factors bind to their receptors, receptor-associated JAKs become activated through trans-phosphorylation.
- Activated JAKs then phosphorylate specific tyrosine residues on the receptor chains, creating docking sites for STAT (Signal Transducer and Activator of Transcription) proteins. STATs bind to these phosphotyrosine sites through their SH2 domains and are subsequently phosphorylated by JAKs. This phosphorylation enables STAT dimerization through reciprocal SH2-phosphotyrosine interactions.
- STAT dimers then translocate to the nucleus, where they bind to specific DNA sequences and regulate gene transcription. Different STAT proteins (STAT1-6) respond to distinct cytokines and activate specific sets of target genes. This specificity allows for precise control of cellular responses to different stimuli.
- The pathway is tightly regulated at multiple levels. Negative regulators include SOCS (Suppressors of Cytokine Signaling) proteins, which are induced by STATs and provide negative feedback, and protein tyrosine phosphatases that remove activating phosphorylation marks. Nuclear transport and DNA binding of STATs are also regulated.
- Dysregulation of JAK-STAT signaling is implicated in various diseases. Hyperactivation can lead to inflammatory conditions and cancer, while deficiencies can cause immunodeficiency. This understanding has led to the development of JAK inhibitors as therapeutic agents for conditions ranging from rheumatoid arthritis to myeloproliferative disorders.
