Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, Parkville, 3052, VIC, Australia.
Immunity. 2012 Feb 24;36(2):239-50. doi: 10.1016/j.immuni.2011.12.015.
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 noncompetitive mechanism, making it a template for the development of specific and effective inhibitors to treat JAK-based immune and proliferative diseases.
Janus 激酶（JAKs）是控制免疫反应和维持造血的关键效应因子。SOCS3（细胞因子信号转导抑制因子-3）是 JAK 信号的主要调节剂，在这里我们研究了其作用机制的分子基础。我们发现 SOCS3 通过 JAK 特有的进化保守基序结合并直接抑制 JAK1、JAK2 和 TYK2 的催化结构域，但不能抑制 JAK3。该基序的突变导致形成不能被 SOCS3 抑制的活性激酶。令人惊讶的是，我们发现 SOCS3 同时结合 JAK 和与其相连的细胞因子受体，揭示了 SOCS 作用中如何产生特异性，并解释了为什么 SOCS3 仅抑制一部分细胞因子。重要的是，SOCS3 通过非竞争性机制抑制 JAK，使其成为开发针对 JAK 的特异性和有效抑制剂来治疗基于 JAK 的免疫和增殖性疾病的模板。
