A direct role for Met endocytosis in tumorigenesis
A direct role for Met endocytosis in tumorigenesis
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DOI：
10.1038/ncb2257
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发表时间：
2011-07-01
影响因子：
21.3
通讯作者：
Kermorgant, Stephanie
中科院分区：
文献类型：
--
作者：
Joffre, Carine;Barrow, Rachel;Kermorgant, Stephanie
受体酪氨酸激酶(RTK)内吞产生的信号的区隔已成为各种细胞功能的主要决定因素。在这里，使用肿瘤相关的甲硫氨酸激活突变，我们证明了内吞作用和致瘤性之间的直接联系。MET突变体表现出增强的内吞/循环活性和降低的降解水平，导致内小体聚集，GTPase rac1激活，肌动蛋白应激纤维丢失和细胞迁移水平增加。阻断内吞作用可抑制突变体的锚定非依赖性生长、体内肿瘤的发生和转移，同时维持其激活。1个耐受Met特异性酪氨酸激酶抑制剂抑制的突变体对内吞作用抑制敏感。因此，Met突变体的致癌性不仅源于激活，还源于其改变的内吞转运，表明内体信号可能是调节RTK依赖的肿瘤发生的关键机制。
Compartmentalization of signals generated by receptor tyrosine kinase (RTK) endocytosis has emerged as a major determinant of various cell functions. Here, using tumour-associated Met-activating mutations, we demonstrate a direct link between endocytosis and tumorigenicity. Met mutants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes, activation oft he GTPase Rac1, loss of actin stress fibres and increased levels of cell migration. Blocking endocytosis inhibited mutants' anchorage-independent growth, in vivo tumorigenesis and metastasis while maintaining their activation. One mutant resistant to inhibition by a Met-specific tyrosine kinase inhibitor was sensitive to endocytosis inhibition. Thus, oncogenicity of Met mutants results not only from activation but also from their altered endocytic trafficking, indicating that endosomal signalling may be a crucial mechanism regulating RTK-dependent tumorigenesis.