A Screen for Conditional Growth Suppressor Genes Identifies the Drosophila Homolog of HD-PTP as a Regulator of the Oncoprotein Yorkie
A Screen for Conditional Growth Suppressor Genes Identifies the Drosophila Homolog of HD-PTP as a Regulator of the Oncoprotein Yorkie
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DOI：
10.1016/j.devcel.2011.04.012
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发表时间：
2011-05-17
影响因子：
11.8
通讯作者：
Moberg, Kenneth H.
中科院分区：
文献类型：
--
作者：
Gilbert, M. Melissa;Tipping, Marla;Moberg, Kenneth H.
哺乳动物癌症依赖于“多重打击”，其中一些促进生长，另一些阻止细胞凋亡。我们筛选了需要协同阻断细胞凋亡以促进组织过度生长的突变，并鉴定了近视（mop），候选肿瘤抑制因子和内体调节因子His结构域蛋白酪氨酸磷酸酶（HD-PTP）的果蝇同系物。我们发现近视调节萨尔瓦多/疣/河马（SWH）肿瘤抑制途径：近视PPxY基序结合保守残基的转录辅激活因子约克的WW域，近视共定位与约克在内涵体。近视控制Yorkie内体缔合和蛋白质水平，最终影响一些Yorkie靶基因的表达。然而，抗凋亡基因diap 1不受影响，这可以解释近视生长表型的条件性。这些数据建立近视作为Yorkie调节器，并暗示近视依赖的Yorkie与内体隔室的关联作为SWH途径的核输出的调节步骤。
Mammalian cancers depend on "multiple hits," some of which promote growth and some of which block apoptosis. We screened for mutations that require a synergistic block in apoptosis to promote tissue overgrowth and identified myopic (mop), the Drosophila homolog of the candidate tumor-suppressor and endosomal regulator His-domain protein tyrosine phosphatase (HD-PTP). We find that Myopic regulates the Salvador/Warts/Hippo (SWH) tumor suppressor pathway: Myopic PPxY motifs bind conserved residues in the WW domains of the transcriptional coactivator Yorkie, and Myopic colocalizes with Yorkie at endosomes. Myopic controls Yorkie endosomal association and protein levels, ultimately influencing expression of some Yorkie target genes. However, the antiapoptotic gene diap1 is not affected, which may explain the conditional nature of the myopic growth phenotype. These data establish Myopic as a Yorkie regulator and implicate Myopic-dependent association of Yorkie with endosomal compartments as a regulatory step in nuclear outputs of the SWH pathway.