TBC1D3: A HOMINOID-SPECIFIC GENE THAT REGULATES GROWTH FACTOR RECEPTOR SIGNALING

TBC1D3：调节生长因子受体信号传导的类人猿特异性基因

• 批准号: 7937782
• 负责人: PHILIP D STAHL
• 金额: $ 31.91万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937782
• 关键词: Basic Science; Binding; Biochemical; Biological Process; Cell Proliferation; Cells; Cellular biology; Cognition; Complex; Data; Development; Disease; Endocytosis; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Event; Evolution; Family; Functional disorder; Genes; Goals; Growth Factor; Growth Factor Receptors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Human; Human Biology; Hydrolysis; IRS1 gene; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Molecular and Cellular Biology; Monomeric GTP-Binding Proteins; Motion; Oncogenes; Pathway interactions; Phosphorylation; Physiology; Process; Protein Isoforms; Proteins; Receptor Signaling; Research; Role; Serine; Signal Pathway; Signal Transduction; Somatomedins; Structure; Testing; Threonine; Tyrosine Phosphorylation Site; Work; gene function; human disease; mutant; public health relevance; receptor coupling; response; three dimensional structure; trafficking; ubiquitin-protein ligase; Basic Science; Binding; Biochemical; Biological Process; Cell Proliferation; Cells; Cellular biology; Cognition; Complex; Data; Development; Disease; Endocytosis; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Event; Evolution; Family; Functional disorder; Genes; Goals; Growth Factor; Growth Factor Receptors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Human; Human Biology; Hydrolysis; IRS1 gene; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Molecular and Cellular Biology; Monomeric GTP-Binding Proteins; Motion; Oncogenes; Pathway interactions; Phosphorylation; Physiology; Process; Protein Isoforms; Proteins; Receptor Signaling; Research; Role; Serine; Signal Pathway; Signal Transduction; Somatomedins; Structure; Testing; Threonine; Tyrosine Phosphorylation Site; Work; gene function; human disease; mutant; public health relevance; receptor coupling; response; three dimensional structure; trafficking; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The molecular cell biology of human- and hominoid-specific genes is virtually a terra incognita in basic research. Understanding the molecular cell biology of human-specific genes will open a new vista of research of wide import to understanding human biology and disease. TBC1D3 is a widely expressed hominoid-specific gene, and recent work indicates that TBC1D3 is a powerful stimulant of the EGF and IGF-1 receptor pathways. Thus, expression of TBC1D3 promotes cellular proliferation and enhances the activation of Ras in response to growth factors. TBC1D3 contains a TBC domain that interacts with the small GTPase Rab5, a key regulator of endocytosis. We speculate that TBC1D3 may be both a growth factor receptor regulator and a Rab5 effector. This proposal focuses upon defining the biochemical mechanisms that are set in motion by TBC1D3 and result in cell proliferation. In Specific Aim 1, we will carry out a structure-function study to determine domains in TBC1D3 involved in cell localization and in Ras activation. To understand the linkage between TBC1D3 and the Ras pathway, we will identify serine/threonine and tyrosine-phosphorylation sites on TBC1D3 and validate the role TBC1D3-interacting proteins, Grb2 and 14-3-3, in Ras activation. In Specific Aim 2, we will quantify the interaction between TBC1D3 and the Rab5 subfamily of GTPases. By modeling the TBC domain of TBC1D3 using 3-dimensional structures of known TBC domains, we will identify key residues at the TBC1D3:Rab5 interface and test their role in Rab5 binding. To confirm and extend these initial structural studies, the structure of the TBC domain will be solved. In Specific Aim 3, we hypothesize that TBC1D3 stimulates cell signaling/proliferation by modulating IRS1 phosphorylation and via the interaction between TBC1D3 and the E3 ubiquitin ligase Cul7. We will characterize the effect of TBC1D3 on IRS1 phosphorylation and turnover. To understand the role of Cul7 in TBC1D3 function, we will determine the domains that mediate TBC1D3-Cul7 interaction and using deletion mutants, determine the function of the TBC1D3-Cul7 complex. The cell and molecular biology of TBC1D3 may represent a model to understand the evolution of human-specific genes that function to modulate and regulate evolutionarily conserved cell signaling pathways. PUBLIC HEALTH RELEVANCE: TBC1D3 is a hominoid-specific gene that regulates growth factor receptor signaling. TBC1D3 has been shown to be an oncogene and to be over-expressed in certain proliferative disorders. Human specific genes have not been extensively studied in spite of their relevance to the human condition and their potential role in human specific diseases. This work proposes to elucidate the mechanism of action of TBC1D3 at the cellular and molecular level. TBC1D3 may serve as a model for developing an understanding of the function of human-specific genes in regulating complex signaling pathways.

描述（由申请人提供）：人类和人素特异性基因的分子细胞生物学实际上是基础研究中的Terra隐身。了解人类特异性基因的分子细胞生物学将为了解人类生物学和疾病的广泛研究开辟新的研究。 TBC1D3是一种广泛表达的人种特异性基因，最近的工作表明TBC1D3是EGF和IGF-1受体途径的强大兴奋剂。因此，TBC1D3的表达促进了细胞增殖，并增强了RAS对生长因子的响应。 TBC1D3包含一个与小GTPase Rab5相互作用的TBC结构域，GTPase Rab5是内吞作用的关键调节剂。我们推测TBC1D3既可能是生长因子受体调节剂，又是RAB5效应子。该建议的重点是定义由TBC1D3运动并导致细胞增殖的生化机制。在特定目标1中，我们将进行一项结构功能研究，以确定与细胞定位和RAS激活中有关的TBC1D3中的域。为了了解TBC1D3与RAS途径之间的联系，我们将在TBC1D3上鉴定丝氨酸/苏氨酸和酪氨酸磷酸化位点，并验证RAS激活中的TBC1D3相互作用蛋白，GRB2和14-3-3的作用。在特定的目标2中，我们将量化TBC1D3与GTPases的Rab5亚家族之间的相互作用。通过使用已知TBC域的3维结构对TBC1D3的TBC结构域进行建模，我们将在TBC1D3：RAB5接口处识别关键残基并测试其在RAB5结合中的作用。为了确认并扩展这些初始结构研究，将解决TBC结构域的结构。在特定目标3中，我们假设TBC1D3通过调节IRS1磷酸化以及TBC1D3与E3泛素连接酶CUL7的相互作用来刺激细胞信号/增殖。我们将表征TBC1D3对IRS1磷酸化和周转率的影响。为了了解CUL7在TBC1D3函数中的作用，我们将确定介导TBC1D3-CUL7相互作用并使用缺失突变体的域，确定TBC1D3-CUL7复合物的功能。 TBC1D3的细胞和分子生物学可能代表了一个模型，以了解人类特异性基因的演变，该基因的功能调节和调节进化保守的细胞信号传导途径。公共卫生相关性：TBC1D3是一种调节生长因子受体信号传导的人类特异性基因。 TBC1D3已被证明是一种癌基因，并且在某些增生性疾病中过表达。尽管人类特异性基因与人类状况及其在人类特异性疾病中的潜在作用相关，但尚未广泛研究它们。这项工作建议阐明在细胞和分子水平上TBC1D3的作用机理。 TBC1D3可以作为对人类特异性基因在调节复杂信号通路中的功能的理解的模型。