Chadee Deborah N, Kyriakis John M
The Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA.
Cell Cycle. 2004 Oct;3(10):1227-9. doi: 10.4161/cc.3.10.1187. Epub 2004 Oct 19.
The extracellular signal-regulated kinase (ERK) group of MAPKs is essential for cell proliferation, including that stimulated by mitogens, oncogenic ras and raf. The Raf kinases (especially B-Raf) are ERK-specific, mitogen-activated MAP3Ks. Mixed lineage kinase-3 (MLK3) is a MAP3K previously thought to be a selective regulator of the JNK group of MAPKs. Surprisingly, we found that silencing of mlk3 by RNAi suppresses mitogen and cytokine activation not only of JNK but of ERK and p38 as well. Silencing mlk3 also blocks mitogen-stimulated phosphorylation of B-Raf at Thr598 and Ser601-a step required for B-Raf activation. Finally, silencing mlk3 prevents serum-stimulated cell proliferation and the proliferation of tumor cells bearing either oncogenic Ki-Ras or loss of function neurofibromatosis-1 (NF1) or NF2 mutations. The proliferation of tumor cells with activating mutations in B-raf or raf-1 are unaffected by silencing mlk3. These results define a new role for MLK3 in B-Raf activation, ERK signaling and cell proliferation. Accordingly, targeting MLK3 could be beneficial to the treatment of tumors with activated receptor tyrosine kinase or ras mutations, and to the treatment of NF1 or NF2 tumors.
丝裂原活化蛋白激酶（MAPK）家族中的细胞外信号调节激酶（ERK）对于细胞增殖至关重要，包括由丝裂原、致癌性Ras和Raf刺激引起的细胞增殖。Raf激酶（尤其是B-Raf）是ERK特异性的、丝裂原激活的MAP3K。混合谱系激酶-3（MLK3）是一种MAP3K，以前被认为是MAPK家族中JNK组的选择性调节因子。令人惊讶的是，我们发现通过RNA干扰使mlk3沉默不仅会抑制JNK的丝裂原和细胞因子激活，还会抑制ERK和p38的激活。使mlk3沉默还会阻断丝裂原刺激的B-Raf在Thr598和Ser601位点的磷酸化——这是B-Raf激活所必需的一步。最后，使mlk3沉默会阻止血清刺激的细胞增殖以及携带致癌性Ki-Ras或功能丧失性神经纤维瘤病1型（NF1）或NF2突变的肿瘤细胞的增殖。具有B-raf或raf-1激活突变的肿瘤细胞的增殖不受mlk3沉默的影响。这些结果确定了MLK3在B-Raf激活、ERK信号传导和细胞增殖中的新作用。因此，靶向MLK3可能有益于治疗具有活化受体酪氨酸激酶或ras突变的肿瘤，以及治疗NF1或NF2肿瘤。
