JAK2
JAK2 (Janus kinase 2) is the cytoplasmic tyrosine kinase that carries signals from hematopoietic cytokine receptors — erythropoietin, thrombopoietin, GM-CSF — into the STAT transcription pathway.
Function
Cytokine receptors of the type I family lack intrinsic kinase domains; they pair constitutively with JAK2, which waits in an autoinhibited state. Ligand binding brings two receptor-associated JAK2 molecules together, they trans-phosphorylate each other, and the activated kinases phosphorylate receptor tails that recruit STAT transcription factors — STAT5 for erythropoietin signaling — which dimerize and enter the nucleus. The same kinase serves IL-6-family gp130 signaling in some contexts. Negative regulation comes from SOCS proteins, themselves STAT targets, forming a feedback loop.
In cancer
The V617F mutation — a phenylalanine-for-valine substitution that releases the autoinhibition of the pseudokinase domain — is the genetic cause of most myeloproliferative neoplasms: polycythemia vera (nearly all cases), essential thrombocythemia, and primary myelofibrosis (about half). The mutant kinase signals without ligand, and the bone marrow produces blood cells without an erythropoietin or thrombopoietin command. JAK2 inhibitors (ruxolitinib) control disease manifestations; they suppress signaling in all tissues, which limits their depth of effect.
Notes
- Human gene symbol: JAK2; UniProt O60674; 1,132 amino acids; Janus kinase family — two kinase-like domains, one catalytic and one regulatory.