Characterization of a novel TGF-beta signaling component

描述（由申请人提供）：潜在参与TGF-β信号传导的新型膜蛋白的表征在蝇和脊椎动物中，生长因子的TGF-β家族的成员在胚胎模式形成和细胞生长和增殖的调节中起重要作用。在人类中，TGF-β信号通路的各种组分的突变与肿瘤形成之间存在许多强有力的联系。近年来，对TGF-β信号转导和细胞周期阻滞机制的研究取得了很大进展。然而，激活素和TGF-β如何在不同组织中促进和抑制细胞增殖的机制尚不清楚。 果蝇的基因组比脊椎动物少得多。它只编码7个TGF-β-型配体，通过3个I型受体和2个SMAD转录因子进行信号传导。我们发现两种配体dActivin和Anti-Activin通过相同的1/11型受体发出信号，并激活主要由DPP激活的dSMAD 1（MAD）和dSMAD 2。然而，这两种配体在体内表现出相反的作用。当在翅膀中过表达时，通过dSMAD 1的dActivin信号传导促进生长，而通过dSMAD 1的Anti-Activin信号传导也抑制生长。这一结果表明，TGF-β信号通路可能比表征的VII型受体/SMAD通路更复杂。在这个提议中，我们描述了一种新型的膜蛋白，可能在TGF-β信号传导中发挥作用。在遗传筛选中，我们已经分离出一种突变，它与DPP信号传导强烈相互作用，类似于dSMAD 1和Medea。我们的分析表明，突变的基因最有可能编码一个进化高度保守的基因，编码一个跨膜蛋白与多种亚型。我们已经从EMS诱变筛选中获得了该基因的至少四个等位基因，并通过P元件动员获得了另外一个等位基因。最强的等位基因是胚胎致死的，纯合克隆是细胞致死的。该提案的目的是证明这些表型是由这种新型跨膜蛋白的突变引起的，并表征单个突变等位基因的分子性质。该项目具有很大的潜力，有助于对TGF-β信号传导机制和我们对某些癌症发展的理解提供新的见解。它还可能为防治这些疾病提供新的目标。

DESCRIPTION (provided by applicant): Characterization of a novel membrane protein potentially involved in TGF-Beta signaling In both flies and vertebrates, members of the TGF-B family of growth factors play prominent roles in embryonic pattern formation and in the regulation of cell growth and proliferation. In humans, there are many strong links between mutations in various components of TGF-Beta signaling pathways and tumor formation. In recent years, a lot of progress has been made toward understanding the mechanism of TGF-B signaling and cell cycle arrest. However, the mechanisms, how Activins and TGF-Betas can promote and inhibit cell proliferation in different tissues, are not known. Drosophila contains substantially fewer genes than vertebrate genomes. It only encodes seven TGF-Beta-type ligands signaling through three type I receptor and two SMAD transcription factors. We find that two of the ligands, dActivin and Anti-Activin, signal through the same type 1/11receptors and activate both dSMAD1 (MAD), which is primarily activated by DPP, and dSMAD2. However, the two ligands exhibit opposite effects in vivo. When overexpressed in wings, dActivin signaling through dSMAD1 promotes growth, while Anti-Activin also signaling through dSMAD1 inhibits growth. This result indicates that the TGF-Beta signaling pathway may be more complex than the characterized type VII receptor/SMAD pathway. In this proposal, we describe a new type of membrane protein that may function in TGF-Beta signaling. In a genetic screen, we have isolated a mutation that strongly interacts with DPP signaling similarly to dSMAD1 and Medea. Our analysis suggests that the mutated gene most likely encodes an evolutionary highly conserved gene that encodes a transmembrane protein with multiple isoforms. We have obtained at least four alleles of this gene from EMS mutagenesis screens and an additional allele by P-element mobilization. The strongest allele is embryonic lethal, and homozygous clones are cell-lethal. The goal of this proposal is to prove that these phenotypes are caused by mutations in this novel transmembrane protein and to characterize the molecular nature of individual mutant alleles. This project has great potential to contribute new insights into the mechanism of TGF-Beta signaling and our understanding of the development of certain cancers. It may also provide a new target to combat these diseases.