Merlin PAKs a punch.
Merlin PAKs a punch.
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梅林重拳出击。
DOI：
10.1097/00130404-200401000-00002
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Widemann,BrigitteC
中科院分区：
文献类型：
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作者：
Widemann,BrigitteC
在这一期的《癌症杂志》中，Hirokawa等人将膜相关蛋白质与肌动蛋白细胞骨架结合。迄今为止，merlin是merlin/ERM中唯一描述p21激活的丝氨酸苏氨酸激酶（PAK）作为药物开发的重要潜在靶点的成员-已知其作为肿瘤抑制剂起作用的亚家族，并且有趣的是，ezrin最近被鉴定为具有上调Ras信号传导的肿瘤，并且另外对于与神经纤维相关的肿瘤-在人类癌症的转移的发展中至关重要。7-9肿瘤瘤病1型（NF 1）或神经纤维瘤病2型（NF 2），这是显性遗传的肿瘤易感性，是大多数NF 1和NF 2综合征的唯一标准治疗。相关肿瘤是完全手术切除。然而，周围神经鞘肿瘤的发展2，由于大小的原因，很多时候是不可行的，是NF 1的标志，这是常见的（近似位置，这些病变的复杂性。每3500人中就有1人受到影响）。此外，有效的医学治疗，缩小肿瘤与NF 1患者发展其他肿瘤（神经胶质瘤和/或防止其进展，因此极大的兴趣。恶性外周神经鞘瘤，例如-Ras基因产物在细胞中起关键作用），并显示非肿瘤表型。2 NF 1基因的信号转导。激活Ras突变发生在神经纤维蛋白，染色体17 q11。2，350 kb，所有人类癌症的60%，10和Ras途径可以外显子），编码神经纤维蛋白（2818个氨基酸），在没有Ras突变的情况下被上调。因此，含有与Ras活化具有显著同源性的结构域的抑制剂是ras GTP酶活化蛋白（GAP）的合理靶点。3人类唯一的癌症和NF 1。法尼基转移酶抑制剂显示的神经纤维蛋白的功能是负面的，是开发的第一类药物，以抑制调节Ras癌基因信号传导，并增加Ras sig-Ras激活，目前正在进行广泛的naling是关键的发展NF 1相关的临床评价与实体瘤和肿瘤患者。4血液恶性肿瘤，以及在患者相比之下，NF 2的特点是发展NF 1和进行性丛状神经纤维瘤。12-14例双侧听觉雪旺细胞瘤。此外，抑制下游靶点的药物，除此之外，大多数NF 2患者会产生许多Ras，如Raf激酶抑制剂BAY 43-9006，是神经鞘瘤、脑膜瘤，偶尔室管膜瘤-在难治性肿瘤患者中进行临床评价。5虽然NF 2是罕见的（在癌症中约为1。与此相反，肿瘤和转移性脑膜瘤的分子基础经常发生，并且经常显示出merlin的热休克抑制活性并不是NF 2的合性失活。纯合子NF 2突变和分子靶向药物的临床试验也在许多散发性间皮瘤中发现。迄今尚未在NF 2中启动。然而，许多NF 2基因（染色体22 q12）编码梅林或最近的研究有助于这种理解，施万诺米（595个氨基酸），这是密切和模型描述梅林如何可能作为一个相关的埃兹蛋白，根蛋白，和膜突蛋白（ERMs）膜肿瘤抑制开始出现。16，17属于前Merlin的细胞骨架相关蛋白具有三个结构域：FERM结构域（蛋白质4.1超家族的残基）。6 ERM蛋白被认为是1-302）在其N-末端，a-螺旋区（残基到…
In this issue of The Cancer Journal, Hirokawa et al1 membrane-associated proteins to the actin cytoskeleton. To date, merlin is the only member of the merlin/ERM describe the p21-activated serine threonine kinases (PAK) as important potential targets for drug develop-subfamily that is known to function as a tumor suppressor, and interestingly ezrin has recently been identified ment for tumors with upregulated Ras signaling, and in addition for tumors associated with neurofibro-as critical for the development of metastasis in human cancers. 7-9 matosis type 1 (NF1) or neurofibromatosis type 2 (NF2), which are dominantly inherited tumor predisposition The only standard treatment for most NF1-and NF2-syndromes. associated tumors is complete surgical resection. How-The development of peripheral nerve sheath tumors2 ever, many times this is not feasible due to the size, is the hallmark of NF1, which is common (approxi-location, and complexity of these lesions. The developmately 1 in 3500 individuals are affected). In addition, ment of effective medical treatments that shrink tumors patients with NF1 develop other tumors (gliomas and or prevent their progression is therefore of great interest. malignant peripheral nerve sheath tumors, for exam- The Ras gene product plays a critical role in cell ple), and show nontumor phenotypes. 2 The NF1 gene signal transduction. Activating Ras mutations occur in (neurofibromin, chromosome 17q11. 2, 350 kb, 60 30% of all human cancers9, 10 and the Ras pathway may exons), encodes neurofibromin (2818 amino acids), be upregulated in absence of Ras mutations. 10, 11 Inhibiwhich contains a domain with significant homology tion of Ras activation is therefore a rational target for to ras GTPase-activating proteins (GAP). 3 The only human cancers and NF1. Farnesyltransferse inhibitors demonstrated function of neurofibromin is to negatively are among the first class of agents developed to inhibit regulate Ras oncogene signaling, and increased Ras sig-Ras activation, and are currently undergoing extensive naling is critical for the development of NF1 associated clinical evaluation for patients with solid tumors and tumors. 4 hematologic malignancies, as well as in patients with In contrast, NF2 is characterized by the develop-NF1 and progressive plexiform neurofibromas. 12-14 ment of bilateral auditory Schwann cell tumors. In In addition, agents that inhibit downstream targets of addition, most patients with NF2 develop many Ras, such as the Raf kinase inhibitor BAY 43-9006, are Schwannomas, meningiomas, and occasionally ependy-undergoing clinical evaluation in patients with refractory momas. 5 Although NF2 is rare (approximately 1 in cancers. 15 35,000 individuals are affected) sporadic schwannomas In contrast, the molecular basis for tumor and metasand meningiomas occur frequently, and often show ho-tasis suppressing activity of merlin is not well undermozygous inactivation of NF2. Homozygous NF2 muta-stood, and clinical trials with molecularly targeted agents tions are also found in many sporadic mesotheliomas. have not been initiated in NF2 to date. However, many The NF2 gene (chromosome 22q12) encodes merlin or recent studies have contributed to this understanding, schwannomin (595 amino acids), which is closely and models describing how merlin may function as a related to ezrin, radixin, and moesin (ERMs) membrane tumor suppressor begin to emerge. 16, 17 cytoskeleton associated proteins that belong to the pro- Merlin has three domains: a FERM domain (residues tein 4.1 superfamily. 6 The ERM proteins are believed 1-302) in its N-terminus, an a-helical region (residues to …