Structure of a Janus Kinase Finally Revealed

Researchers in California have successfully characterized the structure of Janus kinase (JAK), a signaling protein involved in infection, inflammation, the generation of immune cells and—when dysregulated by mutation—the emergence of blood cancers known as myeloproliferative neoplasms.

The structure also reveals the mechanism by which JAK transmits signals sent by immune cell growth factors, called cytokines.

“The question of how JAKs transmit the cytokine signal has been around for 25 years and has been a huge missing link in our understanding of cell signaling,” says Christopher Garci of the Ludwig Institute for Cancer Research at Stanford University. “But there’s more to this than the basic science finding. The structure also tells us how the mutant JAK works and how it leads to blood cancers.”

Cytokines signal through receptors found on the cell surface that thread through the cell’s outer membrane into its cytoplasm. Each receptor has a single JAK protein in an inactive state attached on the cytoplasm side. Each cytokine protein binds two of these receptors, drawing their attached JAKs together. “When the JAKs are brought close together, they activate one another,” Garcia explained. “That’s the activated complex that gets the signaling engine running.”

Each JAK phosphorylates—or adds a phosphate molecule—to a specific spot on its partner. This activates JAKs, which then phosphorylate the cytokine receptor to which they’re attached. This draws a protein known as STAT to the complex, which transmits the cytokine’s growth-promoting signal.

The structure solved by Garcia’s lab is of the JAKs in their juxtaposed and activated state. “Small pieces of the JAK structure had been published over the years—a toe here, a finger there, an ear there—but nobody had seen what the whole body looked like, so to speak,” said Garcia.

The full structure shows that when drawn together by the cytokine, the JAKs meet at a roughly flattened region in their middle. The change induced by the oncogenic JAK mutation—swapping the smaller amino acid valine for the much larger phenylalanine—falls in the middle of this region. The mutation alters the flat interface between the JAKs, creating a sort of ball and socket connection between the two that makes them adhere far more firmly to one another.

“When people have this mutation—the most classical mutation in blood cancers—the JAKs come together and start working all the time because there’s like a little dab of glue in there that’s bringing them together even when there’s no cytokine around,” Garcia said. They thus continuously transmit growth signals, driving cell proliferation.

This structural information has direct implications for the development of new drugs for myeloproliferative neoplasms, which are currently treated by jakinibs—drugs that target all JAK proteins, not just the mutants that drive cancer. This broad targeting of JAK proteins causes side effects that include anemia and thrombocytopenia, a blood clotting disorder.

“Our model of JAK structure gives us an atomic blueprint for how one could make mutant-selective medicines to treat these cancers,” said Garcia.

Garcia’s group is now working on developing drugs to target V617F mutant JAKs and capturing the structure of the larger JAK-STAT complex and that of the complexes formed between different types of JAKs also involved in cytokine signaling.

The findings were published recently in Science.