ALK is a novel dependence receptor - Potential implications in development and cancer
ALK is a novel dependence receptor - Potential implications in development and cancer
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DOI：
10.4161/cc.6.13.4433
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发表时间：
2007-07-01
期刊：
影响因子：
4.3
通讯作者：
Allouche, Michele
中科院分区：
文献类型：
--
作者：
Allouche, Michele
ALK（间变性淋巴瘤激酶）是一种跨膜受体酪氨酸激酶，最初作为NPM-ALK融合蛋白的一部分被发现，由经常与间变性大细胞淋巴瘤相关的染色体重排引起。天然ALK蛋白通常在发育中表达，并且在较弱的水平下在成人神经系统中表达。我们最近发现ALK是一种新的依赖性受体。因此，在不存在配体的情况下，ALK受体是激酶失活的，并且其表达导致细胞凋亡增强，而由于配体或NPM-ALK中的组成性激酶激活，减少细胞凋亡。未连接/激酶未激活的ALK受体通过其自身被半胱天冬酶切割促进细胞凋亡，这是一种允许暴露促细胞凋亡的细胞外膜胞内结构域的现象。本文从ALK受体依赖性受体功能的角度综述了ALK受体在肿瘤发生发展中的生物学意义。ALK在发育生理学中的双重功能在果蝇的视觉系统中得到说明。在神经系统的这一部分中，存在配体时ALK似乎对轴突导向至关重要，而在不存在配体的情况下，ALK表达可导致发育性神经元凋亡。还发现ALK在神经嵴源性肿瘤如人神经母细胞瘤或胶质母细胞瘤中表达，但其作用尚未完全阐明。然而，过度或组成性ALK酪氨酸激酶活化可导致细胞增殖和存活的失调，因此导致人类癌症，例如淋巴瘤和炎性肌纤维母细胞肿瘤。我们的观察结果可能对治疗携带嵌合或野生型ALK蛋白的ALK阳性肿瘤具有重要意义。
ALK ( anaplastic lymphoma kinase) is a transmembrane receptor tyrosine kinase, initially discovered as part of the NPM - ALK fusion protein, resulting from a chromosomal rearrangement frequently associated with anaplastic large cell lymphomas. The native ALK protein is normally expressed in the developing and, at a weaker level, adult nervous system. We recently demonstrated that ALK is a novel dependence receptor. As such, in the absence of ligand, the ALK receptor is kinase inactive and its expression results in enhanced apoptosis, whereas kinase activation, due to a ligand or constitutive as in NPM - ALK, decreases apoptosis. Unligated/ kinase unactivated ALK receptor facilitates apoptosis via its own cleavage by caspases, a phenomenon allowing the exposure of a proapoptotic juxta - membrane intra - cellular domain. This review summarizes the biological significance of the ALK receptor in cancer and development, in perspective with its dependence receptor function. The dual function of ALK in the physiology of development is illustrated in the visual system of Drosophila. In this part of the nervous system, ALK in the presence of ligand appears essential for axonal guidance, whereas in the absence of ligand, ALK expression can lead to developmental neuronal apoptosis. ALK is also found expressed in neural crest - derived tumors such as human neuroblastomas or glioblastomas but its role is not fully elucidated. However, an excessive or constitutive ALK tyrosine kinase activation can lead to deregulation of cell proliferation and survival, therefore to human cancers such as lymphomas and inflammatory myofibroblastic tumors. Our observations could have important implications in the therapy of ALK - positive tumors harboring the chimeric or wild type ALK protein.