Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Department of Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Cell Rep. 2014 Apr 24;7(2):501-513. doi: 10.1016/j.celrep.2014.03.041. Epub 2014 Apr 13.
The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans, MKNK2, the gene encoding for Mnk2, is alternatively spliced yielding two splicing isoforms with differing last exons: Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38α-MAPK into the nucleus, leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation. Alternatively, Mnk2b is pro-oncogenic and does not activate p38-MAPK, while still enhancing eIF4E phosphorylation. We further show that Mnk2a colocalization with p38α-MAPK in the nucleus is both required and sufficient for its tumor-suppressive activity. Thus, Mnk2a downregulation by alternative splicing is a tumor suppressor mechanism that is lost in some breast, lung, and colon tumors.
激酶 Mnk2 是 MAPK 途径的底物，可磷酸化翻译起始因子 eIF4E。在人类中，编码 Mnk2 的基因 MKNK2 可通过不同的最后外显子进行选择性剪接，产生两种具有不同最后外显子的剪接异构体：Mnk2a，其含有 MAPK 结合域，以及 Mnk2b，其缺乏该域。我们发现 Mnk2a 异构体在乳腺癌、肺癌和结肠癌肿瘤中下调，并且具有肿瘤抑制作用。Mnk2a 可直接与 p38α-MAPK 相互作用、磷酸化、激活并将其易位到细胞核中，导致其靶基因激活，增加细胞死亡并抑制 Ras 诱导的转化。相反，Mnk2b 具有致癌作用，不能激活 p38-MAPK，但仍能增强 eIF4E 的磷酸化。我们进一步表明，Mnk2a 与 p38α-MAPK 在细胞核中的共定位是其肿瘤抑制活性所必需且充分的。因此，通过选择性剪接下调 Mnk2a 是一种肿瘤抑制机制，在一些乳腺癌、肺癌和结肠癌肿瘤中丢失。
