Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity.
Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity.
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DOI：
10.1016/j.immuni.2011.12.015
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发表时间：
2012-02-24
期刊：
影响因子：
32.4
通讯作者：
Nicola NA
中科院分区：
文献类型：
--
作者：
Babon JJ;Kershaw NJ;Murphy JM;Varghese LN;Laktyushin A;Young SN;Lucet IS;Norton RS;Nicola NA
Janus激酶（JAK）是控制免疫应答和维持造血的关键效应子。SOCS 3（Suppressor of Cytokine Signaling-3）是JAK信号传导的主要调节因子，在此我们研究其作用机制的分子基础。我们发现SOCS 3结合并直接抑制JAK 1、JAK 2和TYK 2的催化结构域，但不通过JAK特有的进化保守基序抑制JAK 3。该基序的突变导致形成不能被SOCS 3抑制的活性激酶。令人惊讶的是，我们发现SOCS 3同时结合JAK和它所连接的细胞因子受体，揭示了SOCS作用中如何产生特异性，并解释了为什么SOCS 3只抑制细胞因子的一个子集。重要的是，SOCS 3通过非竞争性机制抑制JAK，使其成为开发特异性和有效抑制剂的模板，以治疗基于JAK的免疫和增殖性疾病。
Janus kinases (JAKs) are key effectors in controlling immune responses and maintaining hematopoiesis. SOCS3 (Suppressor of Cytokine Signaling-3) is a major regulator of JAK signaling and here we investigate the molecular basis of its mechanism of action. We found 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. Surprisingly, we found that 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 non-competitive mechanism, making it a template for the development of specific and effective inhibitors to treat JAK-based immune and proliferative diseases.
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