Cytokine receptor → JAK → STAT → nuclear → transcription. Cytokine binding triggers receptor dimerization → JAK (1/2/3/TYK2) cross-phosphorylation → JAK phosphorylates the receptor cytoplasmic tail → STAT (1-6) recruited via SH2 → STAT phosphorylated → dimerizes → nuclear translocation → DNA binding → gene transcription. Receptor-JAK pairings: IFN-γ → JAK1/2 → STAT1; IL-6 family → JAK1/TYK2 → STAT3; IL-2/4/7/9/15/21 → JAK1/3 → STAT5/6; thrombopoietin/erythropoietin → JAK2 → STAT5. JAK INHIBITORS: tofacitinib (JAK1/3), baricitinib (JAK1/2), upadacitinib (JAK1-selective), ruxolitinib (JAK1/2 — myelofibrosis, PV, GVHD), fedratinib (JAK2). Class warning: MACE / VTE / malignancy (ORAL Surveillance trial).
Organ Systems
immune-hematologic
Pathway Steps
cytokine-receptor-engagement → jak-activation — via receptor dimerization → JAK cross-phosphorylation. Type I/II cytokine receptors have no intrinsic kinase activity — they depend on associated JAKs (JAK1/2/3, TYK2), and ligand-induced dimerization juxtaposes two JAKs for trans-phosphorylation. JAK pairing is receptor-specific (e.g. JAK3 only with the common γ-chain), the basis of selective jakinibs and of the SCID caused by JAK3 loss.
jak-activation → stat-phosphorylation — via JAK phosphorylates receptor cytoplasmic tail + recruits STAT via SH2. Active JAKs phosphorylate the receptor tail, creating SH2 docking sites that recruit STATs (STAT1-6), which JAK then phosphorylates. Which cytokine activates which STAT (IFN→STAT1, IL-6→STAT3, IL-4→STAT6) shapes the response — and the gain-of-function JAK2-V617F drives myeloproliferative neoplasms.
stat-phosphorylation → stat-dimer-nuclear — via STAT dimerization → nuclear translocation. Phosphorylated STATs dimerize via reciprocal SH2–phosphotyrosine bonds and translocate to the nucleus — a strikingly direct membrane-to-nucleus relay with no second-messenger cascade. SOCS proteins (themselves STAT target genes) provide the negative feedback by inhibiting JAKs.
stat-dimer-nuclear → transcription — via STAT dimer binds GAS / ISRE / IFN-stim response elements → cytokine + survival gene expression. STAT dimers bind GAS or ISRE elements to drive cytokine, antiviral, and survival/proliferation genes. The pathway’s centrality to immunity is why jakinibs (tofacitinib, ruxolitinib, baricitinib) treat autoimmune disease and myelofibrosis — and why broad JAK inhibition raises infection and thrombosis risk.