Met Receptors Induce Sam68-dependent Cell Migration by Activation of Alternate Extracellular Signal-regulated Kinase Family Members
Met Receptors Induce Sam68-dependent Cell Migration by Activation of Alternate Extracellular Signal-regulated Kinase Family Members
复制标题
DOI：
10.1074/jbc.m110.211409
复制
发表时间：
2011-06-17
影响因子：
4.8
通讯作者：
Lange, Carol A.
中科院分区：
文献类型：
--
作者：
Locatelli, Alessia;Lange, Carol A.
肝细胞生长因子(HGF)/Met受体信号通路在多种人类恶性肿瘤中不受调控，并在肿瘤发生、肿瘤进展和侵袭性癌症生长中发挥核心作用。同样，细胞粘附标记CD44的表达和剪接改变（即包含变异外显子5，“v5”）与晚期癌症表型相关。我们试图进一步了解HGF如何调节CD44v5的表达。永活的非致瘤性角化细胞（HaCaT）大量表达Met受体和CD44v5跨膜糖蛋白。HGF刺激CD44v5蛋白表达和HaCaT细胞迁移；这些事件需要激活ERK1/2 MAPK模块和Sam68， Sam68是一种参与RNA加工、剪接和v5包合的蛋白质。与HaCaT细胞类似，高度迁移的MDA-MB-231乳腺癌细胞也需要表达Sam68来进行hgf诱导的迁移。然而，MDA-MB-231细胞迁移不依赖于ERK1/2和CD44v5的表达，而是需要ERK5向Sam68发出信号。在两种细胞类型中，Phospho-mutant均能阻断hgf诱导的细胞迁移，而WT-Sam68则不能；MDA-MB-435细胞表现相似。这些结果表明，Sam68作为ERK信号传导到细胞迁移的会聚点；阻断phospho-Sam68可能为转移性肿瘤的治疗性抑制提供新的途径。
The hepatocyte growth factor (HGF)/Met receptor signaling pathway is deregulated in diverse human malignancies and plays a central role in oncogenesis, tumor progression, and invasive cancer growth. Similarly, altered expression and splicing (i.e. inclusion of variant exon 5, "v5") of the cell adhesion marker, CD44, is associated with advanced cancer phenotypes. We sought to further understand how HGF regulates CD44v5 expression. Immortalized nontumorigenic keratinocyte (HaCaT) cells abundantly express both Met receptors and CD44v5 transmembrane glycoproteins. HGF stimulated CD44v5 protein expression and HaCaT cell migration; these events required activation of the ERK1/2 MAPK module and Sam68, a protein involved in RNA processing, splicing, and v5 inclusion. Similar to HaCaT cells, highly migratory MDA-MB-231 breast cancer cells also required Sam68 expression for HGF-induced migration. However, MDA-MB-231 cell migration occurred independently of ERK1/2 and CD44v5 expression and instead required ERK5 signaling to Sam68. Phospho-mutant, but not WT-Sam68, blocked HGF-induced cell migration in both cell types; MDA-MB-435 cells behaved similarly. These results suggest that Sam68 acts as a convergence point for ERK signaling to cell migration; blockade of phospho-Sam68 may provide a new avenue for therapeutic inhibition of metastatic cancers.