Regulation of TGF-beta Signaling and Embryonic Development by GTPases

描述（由申请人提供）：gtpase通过作为调节蛋白质伴侣活性的分子开关来控制关键的细胞过程，如信号转导、转录、有丝分裂、细胞形状和细胞运动。目前对Ras、RhoA等小分子量gtpase的功能已经较为了解，但存在多种大分子量gtpase，其功能尚不清楚。GTPBP1和GTPBP2是独特的、较大的gtpase，与翻译伸长因子EF1-alpha有远亲关系。然而，它们的生化和生物学功能是完全未知的。我们已经取得了突破，发现GTPBP1和GTPBP2与Smad蛋白相互作用，Smad蛋白是转化生长因子-¿（TGF¿）超家族的主要信号转导。在胚胎和培养细胞实验中，GTPBP2特别增强BMP和TGF - γ信号的结/激活分支的信号传导。GTPBP基因在爪蟾胚胎发生早期以及随后的体细胞、血液、心脏和神经系统的器官发生过程中表达。用反义寡核苷酸阻断胚胎发育中的内源性GTPBP 1或2会破坏中胚层分化、机体模式和器官发生。在本次资助中，我们拟研究GTPBP 1和2如何调节TGF¿信号和早期脊椎动物发育。目的1将定义GTPBPs和Smads相互作用的特异性和分子基础。目的2将研究GTPBPs如何影响BMP和节点/激活素信号，使用分化和报告基因检测。目的3将通过功能的获得和丧失来研究GTPBPs在爪蟾胚胎中的发育作用，并开始寻找GTPBPs与上游途径之间的联系。TGF¿超家族控制着细胞的生长、死亡、分化和发育，异常的TGF¿信号会导致癌症、高血压、纤维化等疾病和出生缺陷。同样，gtp酶异常会导致癌症、多种疾病和出生缺陷。因此，TGF¿信号蛋白和gtp酶是流行的药物靶点。功能失调的GTPBP2 /2是否影响疾病尚不清楚，但最近在胶质母细胞瘤（一种几乎无法治愈的脑癌）中发现了GTPBP2的染色体易位。我们的研究将提供关于GTPBP的重要信息，这些信息可能最终转化为临床治疗由异常TGF¿或GTPBP信号引起的疾病。

DESCRIPTION (provided by applicant): GTPases govern critical cellular processes such as signal transduction, transcription, mitosis, cell shape and cell movement by acting as molecular switches that regulate activity of protein partners. The functions of small GTPases such as Ras and RhoA are relatively well understood, but there exists a variety of large molecular weight GTPases whose functions are poorly characterized. GTPBP1 and GTPBP2 are unique, large GTPases, distantly related to translation elongation factor EF1-alpha. Their biochemical and biological functions, however, are completely unknown. We have made a breakthrough by discovering that GTPBP1 and GTPBP2 interact with Smad proteins, the principal signal transducers for the Transforming Growth Factor-¿, (TGF¿) superfamily. GTPBP2 in particular enhances signaling by the BMP and nodal/activin branches of TGF¿ signaling in embryo and cultured cell assays. The GTPBP genes are expressed during early Xenopus embryogenesis and during subsequent organogenesis of somites, blood, heart and nervous system. Blocking endogenous GTPBP 1 or 2 in developing embryos with antisense oligonucleotides disrupts mesoderm differentiation, body patterning and organogenesis. In this grant, we propose to investigate how GTPBP 1 and 2 regulate TGF¿ signaling and early vertebrate development. Aim 1 will define the specificity and molecular basis of interaction between GTPBPs and Smads. Aim 2 will investigate how GTPBPs influence BMP and nodal/activin signaling, using differentiation and reporter gene assays. Aim 3 will investigate the developmental roles of the GTPBPs in Xenopus embryos by gain and loss of function, and we will begin a search for links between GTPBPs and upstream pathways. The TGF¿ superfamily controls cell growth, cell death, differentiation and development, and abnormal TGF¿ signaling causes cancer, hypertension, fibroses and other diseases and birth defects. Likewise, abnormalities in GTPases cause cancer, a wide range of diseases, and birth defects. Thus, TGF¿ signaling proteins and GTPases are popular drug targets. Whether dysfunctional GTPBP1/2 affect disease is not known, but a chromosomal translocation of GTPBP2 has recently been identified in glioblastoma, a nearly incurable brain cancer. Our studies will provide crucial information about GTPBPs which may eventually translate into clinical treatments for diseases caused by abnormal TGF¿ or GTPBP signaling.