Life Sciences Research Unit, University of Luxembourg, 162A, av. de la Faïencerie, 1511 Luxembourg, Luxembourg.
J Cell Mol Med. 2010 Mar;14(3):504-27. doi: 10.1111/j.1582-4934.2010.01018.x. Epub 2010 Jan 28.
Gain-of-function mutations in the genes encoding Janus kinases have been discovered in various haematologic diseases. Jaks are composed of a FERM domain, an SH2 domain, a pseudokinase domain and a kinase domain, and a complex interplay of the Jak domains is involved in regulation of catalytic activity and association to cytokine receptors. Most activating mutations are found in the pseudokinase domain. Here we present recently discovered mutations in the context of our structural models of the respective domains. We describe two structural hotspots in the pseudokinase domain of Jak2 that seem to be associated either to myeloproliferation or to lymphoblastic leukaemia, pointing at the involvement of distinct signalling complexes in these disease settings. The different domains of Jaks are discussed as potential drug targets. We present currently available inhibitors targeting Jaks and indicate structural differences in the kinase domains of the different Jaks that may be exploited in the development of specific inhibitors. Moreover, we discuss recent chemical genetic approaches which can be applied to Jaks to better understand the role of these kinases in their biological settings and as drug targets.
在各种血液疾病中发现了编码 Janus 激酶的基因的功能获得性突变。Jak 由一个 FERM 结构域、一个 SH2 结构域、一个假激酶结构域和一个激酶结构域组成，Jak 结构域的复杂相互作用参与了催化活性的调节和与细胞因子受体的结合。大多数激活突变发生在假激酶结构域。在这里，我们在各自结构模型的背景下介绍最近发现的突变。我们描述了 Jak2 假激酶结构域中的两个结构热点，这些热点似乎与骨髓增生或淋巴母细胞白血病有关，这表明在这些疾病环境中涉及不同的信号复合物。讨论了 Jak 的不同结构域作为潜在的药物靶点。我们介绍了目前针对 Jak 的抑制剂，并指出了不同 Jak 的激酶结构域中的结构差异，这些差异可能在开发特异性抑制剂时得到利用。此外，我们还讨论了最近的化学遗传方法，这些方法可应用于 Jak 以更好地了解这些激酶在其生物学环境中的作用以及作为药物靶点。
