RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas
RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas
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DOI：
10.1158/0008-5472.can-06-2301
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Lanfrancone, Luisa
中科院分区：
文献类型：
--
作者：
Fagiani, Ernesta;Giardina, Giuseppina;Lanfrancone, Luisa
衔接蛋白的Src同源性和胶原（Src）家族包括由哺乳动物中的三个基因座（She、Rai和Sli）编码的六种Shc样蛋白。Shc样蛋白是酪氨酸激酶底物，其调节多种信号通路和细胞功能，包括Ras和增殖（p52/p46 Shc）、磷脂酰肌醇3-激酶和存活（p54 Rai）以及线粒体通透性转换和凋亡（p66 Shc）。在这里，我们报告的识别，克隆和序列特征的Shc家族的一个新成员，我们称之为RaLP。RaLP编码一种69 kDa的蛋白质，其特征在于CH 2-PTB-CH 1-SH 2模块化，典型的She蛋白家族，并且在成人组织中仅在黑色素瘤中表达。在黑色素瘤进展过程中的RaLP表达的分析显示，在正常黑色素细胞和良性痣低表达，而高水平的RaLP蛋白被发现在从径向生长阶段的过渡到垂直生长阶段和转移性黑色素瘤，当肿瘤细胞获得迁移能力和侵袭潜力。值得注意的是，通过RNA干扰沉默转移性黑色素瘤中的RaLP表达减少了体内肿瘤发生。对RaLP在黑色素瘤信号转导途径中的分析揭示了（a）当在RaLP阴性黑色素细胞和非转移性黑色素瘤细胞中异位表达时，其作为活化的胰岛素样生长因子-1和表皮生长因子受体的底物发挥作用，并增加Ras/促分裂原活化蛋白激酶（MAPK）信号传导和细胞迁移，而（B）其在RaLP阳性黑色素瘤细胞中的沉默消除体外细胞迁移，而不影响MAPK信号传导，表明RaLP激活黑色素瘤中Ras依赖性和Ras非依赖性迁移途径。这些发现表明RaLP是转移性黑色素瘤的特异性标志物，是黑色素瘤细胞获得迁移表型的关键决定因素，也是新型抗黑色素瘤治疗策略的潜在靶点。
The Src homology and collagen (Src) family of adaptor proteins comprises six Shc-like proteins encoded by three loci in mammals (She, Rai, and Sli). Shc-like proteins are tyrosine kinase substrates, which regulate diverse signaling pathways and cellular functions, including Ras and proliferation (p52/p46Shc), phosphatidylinositol 3-kinase and survival (p54Rai), and mitochondrial permeability transition and apoptosis (p66Shc). Here, we report the identification, cloning, and sequence characterization of a new member of the Shc family that we termed RaLP. RaLP encodes a 69-kDa protein characterized by the CH2-PTB-CH1-SH2 modularity, typical of the She protein family, and expressed, among adult tissues, only in melanomas. Analysis of RaLP expression during the melanoma progression revealed low expression in normal melanocytes and benign nevi, whereas high levels of RaLP protein were found at the transition from radial growth phase to vertical growth phase and metastatic melanomas, when tumor cells acquire migratory competence and invasive potential. Notably, silencing of RaLP expression in metastatic melanomas by RNA interference reduced tumorigenesis in vivo. Analysis of RaLP in melanoma signal transduction pathways revealed that (a) when ectopically expressed in RaLP-negative melanocytes and nonmetastatic melanoma cells, it functions as a substrate of activated insulin-like growth factor-1 and epidermal growth factor receptors and increases Ras/ mitogen-activated protein kinase (MAPK) signaling and cell migration, whereas (b) its silencing in RaLP-positive melanoma cells abrogates cell migration in vitro, without affecting MAPK signaling, suggesting that RaLP activates both Ras-dependent and Ras-independent migratory pathways in melanomas. These findings indicate that RaLP is a specific marker of metastatic melanomas, a critical determinant in the acquisition of the migratory phenotype by melanoma cells, and a potential target for novel anti-melanoma therapeutic strategies.