Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface.
Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface.
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DOI：
10.1101/gad.317354.118
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发表时间：
2018-09-01
影响因子：
10.5
通讯作者：
McClatchey AI
中科院分区：
文献类型：
--
作者：
Chiasson-MacKenzie C;Morris ZS;Liu CH;Bradford WB;Koorman T;McClatchey AI
在这项研究中，基亚松 - 麦肯齐等人表明，神经纤维瘤病2型（NF2）抑癌基因产物神经鞘蛋白（merlin）的缺失，通过一种涉及皮质埃兹蛋白（ezrin）增加、肌动球蛋白改变以及富含胆固醇的细胞膜稳定的机制，使细胞膜与细胞骨架的界面易于发生表皮生长因子（EGF）诱导的巨胞饮作用。他们的研究为巨胞饮摄取和处理的基本机制提供了新的见解，并提出了干预或利用NF2突变及其他肿瘤中巨胞饮作用的新方法。
质膜的结构和生化特性受其与下方皮质细胞骨架的紧密联系所支配。NF2抑癌基因产物merlin以及与之密切相关的膜 - 细胞骨架连接蛋白ezrin，共同构建了膜 - 细胞骨架界面，这是一个关键的细胞区域，既对生长因子受体起调节作用，同时也受其调控。这种尚未被充分理解的相互关系的一个例子就是巨胞饮作用，这是一种古老的营养摄取和膜重塑过程，既能被生长因子触发，又能调控受体的可利用性。我们发现，merlin的缺失通过一种涉及皮质ezrin增加、肌动球蛋白改变以及富含胆固醇的细胞膜稳定的机制，使细胞膜 - 细胞骨架界面易于发生EGF诱导的巨胞饮作用。这些变化深刻改变了merlin缺陷细胞中EGF受体（EGFR）的运输，有利于增加其异源二聚化伙伴ErbB2的膜水平，促进非网格蛋白依赖的内化及再循环。我们的研究表明，与Ras转化细胞不同，merlin缺陷细胞并不依赖巨胞饮对蛋白质的清除作用，而是利用巨胞饮进行受体再循环。最后，我们提供的证据表明，NF2缺陷细胞的巨胞饮能力可用于治疗性摄取。这项工作为巨胞饮摄取和处理的基本机制提供了新的见解，并提出了干预或利用NF2突变及其他肿瘤中巨胞饮作用的新方法。
In this study, Chiasson-MacKenzie et al. show that merlin deficiency primes the membrane:cytoskeleton interface for EGF-induced macropinocytosis via a mechanism involving increased cortical ezrin, altered actomyosin, and stabilized cholesterol-rich membranes. Their study provides new insight into fundamental mechanisms of macropinocytotic uptake and processing and suggests new ways to interfere with or exploit macropinocytosis in NF2 mutant and other tumors. 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 NF2 mutant and other tumors.
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影响因子：
64.5
作者：
Drees, F;Pokutta, S;Weis, WI
通讯作者：
Weis, WI
影响因子：
82.9
作者：
Davidson SM;Jonas O;Keibler MA;Hou HW;Luengo A;Mayers JR;Wyckoff J;Del Rosario AM;Whitman M;Chin CR;Condon KJ;Lammers A;Kellersberger KA;Stall BK;Stephanopoulos G;Bar-Sagi D;Han J;Rabinowitz JD;Cima MJ;Langer R;Vander Heiden MG
通讯作者：
Vander Heiden MG
影响因子：
7.7
作者：
Bloomfield G;Traynor D;Sander SP;Veltman DM;Pachebat JA;Kay RR
通讯作者：
Kay RR
DOI：
10.1146/annurev-cellbio-100616-060739
发表时间：
2017-10-06
影响因子：
11.3
作者：
Devreotes PN;Bhattacharya S;Edwards M;Iglesias PA;Lampert T;Miao Y
通讯作者：
Miao Y
影响因子：
4.2
作者：
Bertelsen V;Stang E
通讯作者：
Stang E