State Key Laboratory of Bio-membrane and Membrane Bio-engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China.
Cell Death Dis. 2013 Oct 17;4(10):e870. doi: 10.1038/cddis.2013.403.
Filopodia, which are actin-rich finger-like membrane protrusions, have an important role in cell migration and tumor metastasis. Here we identify 13 novel calumenin (Calu) isoforms (Calu 3-15) produced by alternative splicing, and find that Calu-15 promotes filopodia formation and cell migration. Calu-15 shuttles between the nucleus and cytoplasm through interacting with importin α, Ran GTPase, and Crm1. The phosphorylation of the threonine at position 73 (Thr-73) by casein kinase 2 (CK2) is essential for the nuclear import of Calu-15, and either Thr-73 mutation or inhibition of CK2 interrupts its nuclear localization. In the nucleus, Calu-15 increases the transcription of growth differentiation factor-15 (GDF-15), a member of the transforming growth factor-β (TGF-β) superfamily, via binding to its promoter region. Furthermore, Calu-15 induces filopodia formation mediated by GDF-15. Together, we identify that Calu-15, a novel isoform of Calu with phosphorylation-dependent nuclear localization, has a critical role in promoting filopodia formation and cell migration by upregulating the GDF-15 transcription.
丝状伪足是富含肌动蛋白的指状细胞膜突起，在细胞迁移和肿瘤转移中具有重要作用。在这里，我们鉴定了 13 种新型钙网蛋白（Calu）剪接异构体（Calu3-15），并发现 Calu-15 促进了丝状伪足的形成和细胞迁移。Calu-15 通过与 importin α、Ran GTPase 和 Crm1 相互作用，在核和细胞质之间穿梭。由酪蛋白激酶 2（CK2）磷酸化的第 73 位苏氨酸（Thr-73）对于 Calu-15 的核输入是必不可少的，并且 Thr-73 突变或 CK2 的抑制都会中断其核定位。在核内，Calu-15 通过与生长分化因子 15（GDF-15）的启动子区域结合，增加转化生长因子-β（TGF-β）超家族成员 GDF-15 的转录。此外，Calu-15 通过 GDF-15 诱导丝状伪足的形成。总之，我们鉴定出 Calu-15 是 Calu 的一种新型剪接异构体，具有依赖磷酸化的核定位，通过上调 GDF-15 转录在促进丝状伪足形成和细胞迁移中发挥关键作用。
