Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA.
Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA.
Int J Mol Sci. 2023 Apr 6;24(7):6805. doi: 10.3390/ijms24076805.
Overactive Janus kinases (JAKs) are known to drive leukemia, making them well-suited targets for treatment. We sought to identify new JAK-activating mutations and instead found a JAK1-inactivating pseudokinase mutation, V666G. In contrast to other pseudokinase mutations that canonically lead to an active kinase, the JAK1 V666G mutation led to under-activation seen by reduced phosphorylation. To understand the functional role of JAK1 V666G in modifying kinase activity we investigated its influence on other JAK kinases and within the Interleukin-2 pathway. JAK1 V666G not only inhibited its own activity, but its presence could inhibit other JAK kinases. These findings provide new insights into the potential of JAK1 pseudokinase to modulate its own activity, as well as of other JAK kinases. Thus, the features of the JAK1 V666 region in modifying JAK kinases can be exploited to allosterically inhibit overactive JAKs.
已知过度活跃的 Janus 激酶（JAKs）可驱动白血病，使其成为治疗的理想靶点。我们试图寻找新的 JAK 激活突变，但却发现了一个 JAK1 失活的假激酶突变，V666G。与其他经典地导致激酶活性的假激酶突变相反，JAK1 V666G 突变导致磷酸化减少，从而导致活性降低。为了了解 JAK1 V666G 在改变激酶活性中的功能作用，我们研究了它对其他 JAK 激酶和白细胞介素-2 途径的影响。JAK1 V666G 不仅抑制自身活性，而且其存在还可以抑制其他 JAK 激酶。这些发现为 JAK1 假激酶调节自身活性以及其他 JAK 激酶的潜力提供了新的见解。因此，可以利用 JAK1 V666 区域的特征来变构抑制过度活跃的 JAK。
