The BRAF^V600E mutation occurs in more than 50% of cutaneous melanomas, and results in the constitutive activation of the mitogen-activated protein kinases (MAPK) pathway. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) are downstream effectors of the activated MAPK pathway, and important molecular targets in invasive and metastatic cancer. Despite the well-known role of MNK1 in regulating mRNA translation, little is known concerning the impact of its aberrant activation on gene transcription. Here, we show that changes in the activity, or abundance, of MNK1 result in changes in the expression of pro-oncogenic and pro-invasive genes. Among the MNK1-upregulated genes, we identify Angiopoietin-like 4 (ANGPTL4), which in turn promotes an invasive phenotype via its ability to induce the expression of matrix metalloproteinases (MMPs). Using a pharmacologic inhibitor of MNK1/2, SEL201, we demonstrate that BRAF^V600E-mutated cutaneous melanoma cells are reliant on MNK1/2 for invasion and lung metastasis.

BRAF ^V600E突变发生在超过 50% 的皮肤黑色素瘤中，并导致丝裂原激活蛋白激酶 (MAPK) 通路的组成型激活。 MAP 激酶相互作用丝氨酸/苏氨酸蛋白激酶 1 和 2 (MNK1/2) 是激活的 MAPK 通路的下游效应器，也是侵袭性和转移性癌症的重要分子靶标。尽管 MNK1 在调节 mRNA 翻译中的作用众所周知，但其异常激活对基因转录的影响却知之甚少。在这里，我们发现 MNK1 活性或丰度的变化会导致促癌基因和促侵袭基因表达的变化。在 MNK1 上调基因中，我们发现了血管生成素样 4 ( ANGPTL4 )，它反过来通过诱导基质金属蛋白酶 (MMP) 表达的能力促进侵袭表型。使用 MNK1/2 的药理学抑制剂 SEL201，我们证明BRAF ^V600E突变的皮肤黑色素瘤细胞依赖于 MNK1/2 进行侵袭和肺转移。