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首页> 外文期刊>International Journal of Molecular Sciences >Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells
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Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells

机译：过度活跃的RAS / PI3-K / MAPK信号级联在Nf1单体不足的间充质干细胞/祖细胞的迁移和粘附中

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Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs) results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1+/−) mice. Nf1+/− MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT) MSPCs. Additionally, Nf1+/− MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1+/− MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K) and mitogen activated protein kinase (MAPK) signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs.
机译：1型神经纤维瘤病（NF1）是一种常染色体显性疾病，由NF1抑癌基因的突变引起，这种突变影响约3000名个体中的1名。 NF1患者患有一系列恶性和非恶性表现，例如丛状神经纤维瘤和骨骼异常。我们先前证明间充质干/祖细胞（MSPC）中的Nf1单倍体功能不足会导致成骨细胞分化受损，这可能与NF1患者的骨骼表现有关。在这里，我们试图进一步确定Nf1在调节Nf1单倍不足（Nf1 + /-/-）小鼠的MSPC迁移和粘附中的作用。与野生型（WT）MSPC相比，Nf1 +/- MSPC显示出增加的核质比，增加的迁移和增加的肌动蛋白聚合。另外，Nf1 +/- MSPCs显着增强了对纤连蛋白的细胞粘附性，对CH271具有选择性亲和力，并且其互补受体CD49e过表达。与WT MSPC相比，Nf1 +/- MSPCs还显示了磷酸肌醇3-激酶（PI3-K）和有丝分裂原活化蛋白激酶（MAPK）信号通路的过度激活，两者均明显降低。它们的药理抑制剂分别为LY294002和PD0325901。总的来说，我们的研究表明PI3-K和MAPK信号通路在Nf1单倍体不足MSPC的增强迁移和粘附中起着重要作用。

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