Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes Dev. 2018 Sep 1;32(17-18):1201-1214. doi: 10.1101/gad.317354.118. Epub 2018 Aug 24.
The architectural and biochemical features of the plasma membrane are governed by its intimate association with the underlying cortical cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor merlin and closely related membrane:cytoskeleton-linking protein ezrin organize the membrane:cytoskeleton interface, a critical cellular compartment that both regulates and is regulated by growth factor receptors. An example of this poorly understood interrelationship is macropinocytosis, an ancient process of nutrient uptake and membrane remodeling that can both be triggered by growth factors and manage receptor availability. We show that merlin deficiency primes the membrane:cytoskeleton interface for epidermal growth factor (EGF)-induced macropinocytosis via a mechanism involving increased cortical ezrin, altered actomyosin, and stabilized cholesterol-rich membranes. These changes profoundly alter EGF receptor (EGFR) trafficking in merlin-deficient cells, favoring increased membrane levels of its heterodimerization partner, ErbB2; clathrin-independent internalization; and recycling. Our work suggests that, unlike Ras transformed cells, merlin-deficient cells do not depend on macropinocytic protein scavenging and instead exploit macropinocytosis for receptor recycling. Finally, we provide evidence that the macropinocytic proficiency of NF2-deficient cells can be used for therapeutic uptake. This work provides new insight into fundamental mechanisms of macropinocytic uptake and processing and suggests new ways to interfere with or exploit macropinocytosis in mutant and other tumors.
质膜的结构和生化特征由其与基底皮质细胞骨架的紧密联系决定。神经纤维瘤病 2 型（NF2）肿瘤抑制因子 Merlin 和密切相关的膜-细胞骨架连接蛋白 ezrin 组织了膜-细胞骨架界面，这是一个关键的细胞区室，既受生长因子受体的调节，也受其调节。这种相互关系理解不足的一个例子是巨胞饮作用，这是一种古老的营养物质摄取和膜重塑过程，既可以被生长因子触发，也可以管理受体的可用性。我们表明，Merlin 缺陷通过涉及皮质 ezrin 增加、肌动球蛋白改变和富含胆固醇的膜稳定的机制，为表皮生长因子（EGF）诱导的巨胞饮作用使质膜-细胞骨架界面做好准备。这些变化深刻地改变了 Merlin 缺陷细胞中表皮生长因子受体（EGFR）的运输，有利于其异二聚体伴侣 ErbB2 的膜水平增加；网格蛋白非依赖性内化；和回收。我们的工作表明，与 Ras 转化细胞不同， Merlin 缺陷细胞不依赖于巨胞饮蛋白的清除，而是利用巨胞饮作用进行受体回收。最后，我们提供了证据表明 NF2 缺陷细胞的巨胞饮能力可用于治疗性摄取。这项工作为巨胞饮作用的摄取和加工的基本机制提供了新的见解，并为在突变体和其他肿瘤中干扰或利用巨胞饮作用提供了新的方法。
