Endocytosis and Cancer
Endocytosis and Cancer
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DOI：
10.1101/cshperspect.a016949
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发表时间：
2013-12-01
影响因子：
7.2
通讯作者：
Yarden, Yosef
中科院分区：
文献类型：
--
作者：
Mellman, Ira;Yarden, Yosef
内吞作用需要有选择地将细胞表面蛋白，如细胞因子和黏附成分的受体，包装在细胞质小泡(内小体)中。决定内化蛋白命运的一系列分选事件，无论是在溶酶体中降解还是循环回到质膜，都依赖于内在序列基序、翻译后修饰(例如，磷酸化和泛素化)以及Rab GTP酶和磷酸肌醇结合蛋白的瞬时组装。这一多组分的过程在癌细胞中得到增强和扭曲；我们回顾了使癌症的两个主要驱动因素--p53和RAS--偏向整合素和受体酪氨酸激酶(RTK)循环的机制。同样，癌细胞的钙粘附素和其他连接蛋白会不断地从细胞表面移除，从而扰乱组织的极性并激发运动表型。能够逃避Cbl介导的泛素化的RTK的突变形式，以及野生型形式的过度表达和各种有缺陷的反馈调节环，在肿瘤中经常被检测到。最后，我们描述了利用癌症特殊的内吞系统的药理学尝试，以利于有效的患者治疗。
Endocytosis entails selective packaging of cell-surface proteins, such as receptors for cytokines and adhesion components, in cytoplasmic vesicles (endosomes). The series of sorting events that determines the fate of internalized proteins, either degradation in lysosomes or recycling back to the plasma membrane, relies on intrinsic sequence motifs, posttranslational modifications (e. g., phosphorylation and ubiquitination), and transient assemblies of both Rab GTPases and phosphoinositide-binding proteins. This multicomponent process is enhanced and skewed in cancer cells; we review mechanisms enabling both major drivers of cancer, p53 and Ras, to bias recycling of integrins and receptor tyrosine kinases (RTKs). Likewise, cadherins and other junctional proteins of cancer cells are constantly removed from the cell surface, thereby disrupting tissue polarity and instigating motile phenotypes. Mutant forms of RTKs able to evade Cbl-mediated ubiquitination, along with overexpression of the wild-type forms and a variety of defective feedback regulatory loops, are frequently detected in tumors. Finally, we describe pharmacological attempts to harness the peculiar endocytic system of cancer, in favor of effective patient treatment.