JAK2 signaling in myeloproliferative disorders (MPD).

Activation of JAK2 occurs physiologically when Epo binds to the EpoR and results in an activated dimeric conformation to the receptor (A). A number of signaling molecules (such as STAT5) become recruited to the phosphorylated receptor and JAK2. These molecules subsequently become themselves phosphorylated and activated. This results in specific gene expression pattern leading to proliferation, survival and differentiation of erythroid progenitors. At the same time, negative regulators such as SOCS and CIS proteins are induced and recruited to the receptor as well as phosphatases, such as Shp1, which negatively modulates signaling. The V617 JAK2 mutant (depicted as a modular protein in B and C) is able to bind to the cytoplasmic domain of EpoR (B) and presumably to the cytoplasmic domain of other cytokine receptors (C) and to phosphorylate discrete tyrosine (Y) residues. The V617F mutation is shown as (*) in the pseudokinase domain (B and C), and this mutation presumably activates the kinase domain of the same JAK2 molecule (intramolecular activation). The mutant JAK2 may activate cytokine receptor signaling by scaffolding to the cytoplasmic domain of EpoR and of other JAK2-utilizing cytokine receptors. This might lead to constitutive activation of STAT5, MAP-kinase, phosphatidylinositol-3-kinase (PI-3-kinase) and Akt. Activation of receptor tyrosine kinases such as IGF1 receptor (D) may synergize with the signaling of the V617 JAK2 mutant, and this cross-talk between Janus kinases and receptor tyrosine kinases may contribute to the pathogenesis of MPDs.

Depending on the level of enzymatic activity of the V617 JAK2 mutant, on the precise hematopoietic stem cell (HSC) subset where the mutation originally occurs, and on other genetic events, possibly involving SOCS or phosphatase genes, the V617 JAK2 mutant may lead to polycythemia vera (PV), essential thrombocythemia (ET), or idiopathic myelofibrosis (IMF).