In a March paper in Science, Ludwig Stanford’s Christopher Garcia reported the long-sought structure of a Janus kinase, whose mutation drives blood cancers known as myeloproliferative neoplasms. The structure reveals the mechanism by which Janus kinase-1 (JAK-1) transmits signals, as part of a JAK-STAT signaling complex, when activated by cytokines and how a mutation (V617F) switches JAKs on uncontrollably to cause cancer. The JAK protein is attached to the cytoplasmic tail of the cytokine receptor. Each cytokine protein binds two of these receptors, juxtaposing their attached JAKs and prompting them to activate one another. The new structure shows that the co-activating JAKs meet at a flattened region in their middle. The change induced by the V617F mutation to JAK creates a sort of ball-and-socket connection between the two that makes them adhere far more firmly to one another, switching them on even in the absence of an activating cytokine to transmit growth signals. The finding opens the door to developing targeted small molecules that selectively disrupt the mutant JAKs. Though Chris’s team solved the structure of activated JAK-1, and the V617F mutation is found in JAK-2, the two are sufficiently alike to share a signaling mechanism.
This article appeared in the May 2022 issue of Ludwig Link. Click here to download a copy (PDF, 2MB).