JAKs, Stats, and CK2?

derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Activating mutations in JAK2, a tyrosine kinase that serves as a critical signaling protein for multiple cytokines, are associated with BCR-ABL1–negative myelo-proliferative neoplasms. In this issue of Blood, Zheng and colleagues report that the constitutively activated kinase CK2 binds to JAK2 and is required for JAK-Stat signaling, suggesting that CK2 inhibitors may provide a second, complimentary therapeutic for diseases with elevated JAK2 signaling, such as myeloproliferative neoplasms. 1 J AK family tyrosine kinases (JAK1, JAK2, JAK3, Tyk2) bind to cytokine receptors and are activated on cytokine binding. The activated JAKs phosphorylate tyrosines in themselves and in the associated cytokine receptors. The resulting phosphotyrosines form binding sites for multiple signaling proteins, including the Stat transcription factors that mediate many of the actions of the activating cytokines. 2 JAK2 is activated by more than 15 different cytokines including erythropoi-etin, oncostatin M (OSM), GM-SCF, throm-bopoietin, some interleukins, leukemia inhibi-tory factor, and IFN-␥ 3 as well as by some G protein– coupled receptors. 4 Activating mutations in JAK2 have been found in patients with myeloproliferative neoplasms, with the most common mutation being V617F. This mutation is present in more than 95% of patients with polycythemia vera (PV), 32% to 57% of patients with essential thrombocythe-mia (ET), and 35% to 50% of patients with primary myelofibrosis (PMF). 3,5 This has made JAK2 an attractive target for therapeutic intervention, and in fact, multiple JAK2 in-hibitors are currently in phase 1, 2, and 3 trials. 3 For these reasons, it is critical to identify the proteins that bind to JAK2 and understand how they regulate and/or mediate JAK2 function. Although quite a few proteins have been identified that are recruited to phosphorylated tyrosines in the cytokine receptors per se, including Stat proteins, very few proteins have been identified that regulate JAK2 signaling as a consequence of binding to JAK2. Zheng and colleagues provide the first evidence that the serine/threonine kinase CK2 binds to JAK2 and is critical for activation of the JAK2-Stat signaling pathway in response to ligand stimulation and for the constitutive activation of JAK2 in cells expressing JAK2 V617F. 1 CK2 is a ubiquitously expressed ki-nase that exists primarily as a tetramer composed of 2 catalytic subunits (CK2␣) and 2 regulatory subunits (CK2␤). CK2 is found in multiple subcellular compartments, and has more than 300 known substrates, many associated with cell viability. 6,7 Zheng et al …