Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Center for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ranchi, Jharkhand, 835205, India.
Oncogene. 2019 May;38(19):3569-3584. doi: 10.1038/s41388-019-0690-0. Epub 2019 Jan 21.
Mixed lineage kinase 3 (MLK3), a MAP3K member has been envisioned as a viable drug target in cancer, yet its detailed function and signaling is not fully elucidated. We identified that MLK3 tightly associates with an oncogene, PAK1. Mammalian PAK1 being a Ste20 (MAP4K) member, we tested whether it is an upstream regulator of MLK3. In contrast to our hypothesis, MLK3 activated PAK1 kinase activity directly, as well as in the cells. Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3. Stable overexpression of PAK1S204A in breast cancer cells, impedes migration, invasion, and NFĸB activity. In vivo breast cancer cell tumorigenesis is significantly reduced in tumors expressing PAK1S204A mutant. These results suggest that mammalian PAK1 does not act as a MAP4K and MLK3-induced direct activation of PAK1 plays a key role in breast cancer tumorigenesis.
混合谱系激酶 3（MLK3），一种 MAP3K 成员，被认为是癌症的一个可行的药物靶点，但它的详细功能和信号通路尚未完全阐明。我们发现 MLK3 与癌基因 PAK1 紧密相关。哺乳动物 PAK1 作为 Ste20（MAP4K）成员，我们测试了它是否是 MLK3 的上游调节剂。与我们的假设相反，MLK3 直接激活 PAK1 的激酶活性，以及在细胞中。尽管 MLK3 可以在 Ser133 和 Ser204 位点上磷酸化 PAK1，但 PAK1S133A 突变体是组成性激活的，而 PAK1S204A 不能被 MLK3 激活。在乳腺癌细胞中稳定过表达 PAK1S204A 可抑制迁移、侵袭和 NFκB 活性。在表达 PAK1S204A 突变体的肿瘤中，体内乳腺癌细胞肿瘤发生显著减少。这些结果表明，哺乳动物 PAK1 不作为 MAP4K，MLK3 诱导的 PAK1 直接激活在乳腺癌肿瘤发生中起着关键作用。
