JAK2STAT

JAK2-STAT is a signaling module that combines the Janus kinase 2 (JAK2) with signal transducers and activators of transcription (STAT) proteins to relay signals from extracellular cytokines to the nucleus. It plays a key role in hematopoiesis and immune responses.

In cells bearing type I or type II cytokine receptors, cytokine binding promotes receptor dimerization and brings bound JAK2 molecules into proximity. Activated JAK2 phosphorylates tyrosine residues on the receptor, creating docking sites for STATs. STAT proteins bind, are phosphorylated, dimerize, and translocate to the nucleus where they regulate transcription of genes controlling proliferation, differentiation, and survival.

Negative regulation is provided by SOCS proteins, phosphatases, and proteasomal degradation, forming feedback loops that limit signaling after cytokine withdrawal.

The pathway influences erythropoiesis, immune cell development, and inflammatory responses. In erythroid cells, erythropoietin receptor signaling activates JAK2-STAT to coordinate red blood cell production.

Mutations in JAK2, especially JAK2 V617F, constitutively activate the pathway and are characteristic of myeloproliferative neoplasms such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2 inhibitors (e.g., ruxolitinib) are used clinically, but may cause anemia, thrombocytopenia, and other adverse effects and do not cure the disease.

JAK2-STAT interacts with other signaling pathways, including MAPK and PI3K-AKT, and is regulated by other JAK family members. Ongoing research aims to improve inhibitors and understand resistance mechanisms.