Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin Luther University of Halle, Halle, Germany.
Cell Adh Migr. 2012 Jul-Aug;6(4):312-8. doi: 10.4161/cam.20628. Epub 2012 Jul 1.
The oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA binding protein 1) controls the cytoplasmic fate of specific target mRNAs including ACTB and CD44. During neural development, IGF2BPs promote neurite protrusion and the migration of neuronal crest cells. In tumor-derived cells, IGF2BP1 enhances the formation of lamellipodia and invadopodia. Accordingly, the de novo synthesis of IGF2BP1 observed in primary malignancies was reported to correlate with increased metastasis and an overall poor prognosis. However, if and how the protein enhances metastasis remains controversial. In recent studies, we reveal that IGF2BP1 promotes the directed migration of tumor-derived cells in vitro by controlling the expression of MAPK4 and PTEN. The IGF2BP1-facilitated inhibition of MAPK4 mRNA translation interferes with MK5-directed phosphorylation of the heat shock protein 27 (HSP27). This limits G-actin sequestering by phosphorylated HSP27, enhances cell adhesion and elevates the velocity of tumor cell migration. Concomitantly, IGF2BP1 promotes the expression of PTEN by interfering with PTEN mRNA turnover. This results in a shift of cellular PtdIns(3,4,5)P 3/PtdIns(4,5)P 2 ratios and enhances RAC1-dependent cell polarization which finally promotes the directionality of tumor cell migration. These findings identify IGF2BP1 as a potent oncogenic factor that regulates the adhesion, migration and invasiveness of tumor cells by modulating intracellular signaling.
癌胚 RNA 结合蛋白 IGF2BP1（IGF2 mRNA 结合蛋白 1）控制特定靶 mRNA（包括 ACTB 和 CD44）的细胞质命运。在神经发育过程中，IGF2BPs 促进神经突的伸出和神经嵴细胞的迁移。在肿瘤衍生的细胞中，IGF2BP1 增强了片状伪足和侵入伪足的形成。因此，在原发性恶性肿瘤中观察到的 IGF2BP1 的从头合成被报道与增加的转移和总体不良预后相关。然而，该蛋白如何增强转移仍然存在争议。在最近的研究中，我们揭示 IGF2BP1 通过控制 MAPK4 和 PTEN 的表达促进肿瘤衍生细胞在体外的定向迁移。IGF2BP1 促进的 MAPK4 mRNA 翻译抑制干扰了热休克蛋白 27（HSP27）的 MK5 定向磷酸化。这限制了磷酸化 HSP27 对 G-肌动蛋白的隔离，增强了细胞黏附并提高了肿瘤细胞迁移的速度。同时，IGF2BP1 通过干扰 PTEN mRNA 周转来促进 PTEN 的表达。这导致细胞内 PtdIns(3,4,5)P3/PtdIns(4,5)P2 比值的变化，并增强 RAC1 依赖性细胞极化，最终促进肿瘤细胞迁移的方向性。这些发现确定 IGF2BP1 是一种有效的致癌因子，通过调节细胞内信号转导来调节肿瘤细胞的黏附、迁移和侵袭性。
