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Discovery May Lead to New Treatments for Myeloproliferative Disorders

By LabMedica International staff writers
Posted on 27 Feb 2012
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A recent paper outlined the molecular basis for the inhibition of Janus kinases (JAKs)--key effectors in controlling immune responses and maintaining blood cell production--by their major regulator SOCS3 (suppressor of cytokine signaling-3).

Mutations in the JAK2 gene that prevent SOCS inhibition have been implicated in polycythemia vera, essential thrombocythemia, and other myeloproliferative disorders. This mutation, a change of valine to phenylalanine at the 617 position, appears to render hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin. On the other hand, loss of Jak2 is lethal by embryonic day 12 in mice. The role of JAK2 in triggering myeloproliferative disorders has elicited drug developers to search for drugs to block its activity. So far, however, clinical trials of candidate drugs have shown limited efficacy and apparent toxicities.

In the current study, investigators at the Walter and Eliza Hall Institute (Parkville, VIC, Australia) investigated the molecular basis of the JAK-SOCS interaction.

They reported in the February 16, 2012, online edition of the journal Immunity that SOCS3 bound and directly inhibited the catalytic domains of JAK1, JAK2, and TYK2 but not JAK3 via an evolutionarily conserved motif unique to JAKs. Mutation of this motif led to the formation of an active kinase that could not be inhibited by SOCS3. SOCS3 simultaneously bound JAK and the cytokine receptor to which it is attached, revealing how specificity is generated in SOCS action and explaining why SOCS3 inhibits only a subset of cytokines. Importantly, SOCS3 inhibited JAKs via a noncompetitive mechanism, making it a template for the development of specific and effective inhibitors to treat JAK-based immune and proliferative diseases.

“JAK proteins are activated in response to blood cell hormones called cytokines and instruct immune cells to respond to infection and inflammation,” said first author Dr. Jeff Babon, laboratory head in the division of structural biology at the Walter and Eliza Hall Institute. “SOCS proteins were discovered at the institute in the early 2000s, and provide a necessary negative feedback response that stops JAKs becoming overactive, which can lead to disease.”

“When JAK2 is mutated, it tells cells to continually multiply. An excessive amount of blood cells of one type are produced, and the bone marrow is overrun, leading to problems with production of other cell types, and eventually bone marrow failure,” said Dr. Babon. “SOCS3 is a key inhibitor of JAK2 proteins in blood and immune cells, but we did not know exactly how the two proteins interacted to suppress JAK2 function. We wanted to identify which site the SOCS3 protein bound to on the JAK2 protein to inhibit its action, and were surprised to find that SOCS3 binds to a unique site on JAK2 and directly inhibits the protein, rather than outcompeting other molecules. The SOCS3 binding site is a previously unknown part of the JAK2 protein which could be exploited as a drug target, with greater specificity than other drugs that are currently in clinical trials for inhibiting JAK2.”

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