Regulation of TGF-beta Signaling and Embryonic Development by GTPases

描述（由申请人提供）：GTP酶通过充当调节蛋白伴侣活性的分子开关，控制关键细胞过程，如信号转导、转录、有丝分裂、细胞形状和细胞运动。小GTP酶如Ras和RhoA的功能相对较好地理解，但存在多种大分子量GTP酶，其功能的表征较差。GTPBP 1和GTPBP 2是独特的大GTP酶，与翻译延伸因子EF 1-α远相关。然而，它们的生物化学和生物学功能完全未知。我们通过发现GTPBP 1和GTPBP 2与Smad蛋白相互作用而取得了突破性进展，Smad蛋白是转化生长因子（TGF）超家族的主要信号转导子。在胚胎和培养细胞测定中，GTPBP 2特别增强BMP和TGF β信号传导的节点/激活素分支的信号传导。GTPBP基因在非洲爪蟾早期胚胎发生和随后的体节、血液、心脏和神经系统器官发生过程中表达。用反义寡核苷酸阻断发育中胚胎中的内源性GTPBP 1或2会破坏中胚层分化、体形成和器官发生。在这项研究中，我们计划研究GTPBP 1和2如何调节TGF β信号传导和早期脊椎动物发育。目的1明确GTPBPs与Smads相互作用的特异性和分子基础。目的2将研究如何GTPBPs影响BMP和nodal/激活素信号，使用分化和报告基因测定。目标3将通过功能的获得和丧失来研究非洲爪蟾胚胎中GTPBPs的发育作用，我们将开始寻找GTPBPs与上游途径之间的联系。TGF？超家族控制细胞生长、细胞死亡、分化和发育，异常的TGF β信号传导导致癌症、高血压、纤维化和其他疾病以及出生缺陷。同样，GTP酶的异常会导致癌症、多种疾病和出生缺陷。因此，TGF β信号传导蛋白和GTP酶是流行的药物靶标。功能失调的GTPBP 1/2是否会影响疾病尚不清楚，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GTPBP 2的染色体易位。我们的研究将提供有关GTPBP的关键信息，这些信息最终可能转化为由异常TGF β或GTPBP信号转导引起的疾病的临床治疗。

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.