Molecular Dissection of Growth Factor Receptor Signaling

生长因子受体信号传导的分子剖析

基本信息

批准号：
7365265
负责人：
AKHILESH PANDEY
金额：
$ 27.64万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-11 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7365265
关键词：
Affect Ankyrin Repeat Ankyrins Apoptosis Binding Biochemical Breast Breast Carcinoma Caenorhabditis elegans Carcinogens Cell Cycle Cell surface Cells Complex Data Development Disruption Dissection Dominant-Negative Mutation Dose Duct (organ) structure EGF gene Embryo Endocytosis Epidermal Growth Factor Receptor FOS gene Family Fibroblasts Growth Factor Growth Factor Inhibition Growth Factor Receptors Human Immunohistochemistry In Vitro Incidence Knock-out Knockout Mice Lead Ligands Literature Malignant Neoplasms Mammary Neoplasms Mammary gland Mass Spectrum Analysis Mediating Methodology Molecular Morphogenesis Multiprotein Complexes Mus Mutate Neoplasm Metastasis Numbers Oncogenic Orthologous Gene PTB Domain Pathway interactions Patient currently pregnant Phosphotransferases Play Protein Dephosphorylation Protein Overexpression Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Proteomics RNA Interference Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Role SAM Domain Signal Pathway Signal Transduction Signaling Molecule Site-Directed Mutagenesis Stable Isotope Labeling Sterility Structure Testing Tissues Transgenic Mice Tyrosine Tyrosine Phosphorylation United States National Institutes of Health adapter protein attenuation base bindin chemical carcinogen dimethylbenzanthracene improved in vivo link protein malignant breast neoplasm member novel numb protein outcome forecast promoter protein expression receptor response tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Dysregulated tyrosine kinase activity is implicated in a large number of human cancers. Several members of the epidermal growth factor receptor family are amplified and overexpressed in human tumors and abrogation of their activity can lead to improved prognosis and survival. Although the mechanisms underlying the mitogenic pathways downstream of receptor tyrosine kinases are quite well understood, little is known about how these proliferative signals are shut off. In a proteomic screen to identify molecules in the EGF receptor pathway, we have previously identified Odin, a novel tyrosine-phosphorylated adapter protein containing PTB, Ankyrin and SAM domains. We have demonstrated that overexpression of Odin leads to inhibition of growth factor-induced signaling and proliferation in fibroblasts. RNAi-based knockdown of Odin ortholog in C. elegans leads to sterility indicating the importance of this evolutionarily conserved molecule. In preliminary studies, we have identified Grb2 as a molecule that interacts with Odin. We hypothesize that Odin acts as a negative regulator of growth factor receptor signaling by binding to Grb2 and disrupting the Grb2/Sos/Ras complex. Based on our preliminary data demonstrating association of Odin with several proteins in an EGF-inducible fashion, we further hypothesize that different domains of Odin participate in the recruitment of this multiprotein complex, which is crucial for Odin function. Finally, we hypothesize that Odin plays a role in transformation of fibroblasts by activated tyrosine kinases and in mammary gland development and tumor formation. The significance of this proposal is that it will allow us to define the biochemical mechanisms that help downregulate growth factor induced signaling as well as elucidate the in vivo relevance of Odin in mammary tissue. A detailed understanding of such inhibitory mechanisms will be crucial for strategies that target intracellular signaling molecules in the treatment of human cancers.

描述（由申请人提供）：酪氨酸激酶活性失调与大量人类癌症有关。表皮生长因子受体家族的几个成员在人类肿瘤中得到扩增和过表达，并且消除其活性会导致预后改善和生存。尽管受体酪氨酸激酶下游的有丝分裂途径的基础机制已被充分了解，但对于如何关闭这些增殖信号是什么知之甚少。在蛋白质组学筛选以鉴定EGF受体途径中的分子中，我们先前已经鉴定出ODIN，ODIN是一种新型的酪氨酸磷酸化衔接蛋白，其中含有PTB，Ankyrin和Sam域。我们已经证明，ODIN的过表达导致抑制生长因子诱导的信号传导和成纤维细胞增殖。秀丽隐杆线虫中基于RNAi的ODIN直系同源物的敲低导致无菌性表明该进化保守的分子的重要性。在初步研究中，我们已经将GRB2确定为与Odin相互作用的分子。我们假设Odin通过与GRB2结合并破坏GRB2/SOS/RAS复合物来充当生长因子受体信号传导的负调节剂。基于我们以EGF诱导的方式证明ODIN与几种蛋白质的关联的初步数据，我们进一步假设Odin的不同领域参与了这种多动蛋白复合物的募集，这对于ODIN功能至关重要。最后，我们假设ODIN通过活性酪氨酸激酶以及乳腺发育和肿瘤形成在成纤维细胞的转化中起作用。该提议的意义在于，它将允许我们定义有助于下调生长因子诱导的信号传导的生化机制，并阐明Odin在乳腺组织中的体内相关性。对这种抑制机制的详细理解对于针对人类癌症治疗细胞内信号分子的策略至关重要。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comprehensive comparison of collision induced dissociation and electron transfer dissociation.

DOI：
10.1021/ac8007785
发表时间：
2008-07-01
期刊：
ANALYTICAL CHEMISTRY
影响因子：
7.4
作者：
Molina, Henrik;Matthiesen, Rune;Kandasamy, Kumaran;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh

Identification of Novel Phosphorylation Motifs Through an Integrative Computational and Experimental Analysis of the Human Phosphoproteome.

通过人类磷酸化蛋白质组的综合计算和实验分析鉴定新型磷酸化基序。

DOI：
10.4172/jpb.1000163
发表时间：
2011
期刊：
Journal of proteomics & bioinformatics
影响因子：
0
作者：
Amanchy,Ramars;Kandasamy,Kumaran;Mathivanan,Suresh;Periaswamy,Balamurugan;Reddy,Raghunath;Yoon,Wan-Hee;Joore,Jos;Beer,MichaelA;Cope,Leslie;Pandey,Akhilesh
通讯作者：
Pandey,Akhilesh

Identification of c-Src tyrosine kinase substrates using mass spectrometry and peptide microarrays.

DOI：
10.1021/pr800198w
发表时间：
2008-09
期刊：
JOURNAL OF PROTEOME RESEARCH
影响因子：
4.4
作者：
Amanchy, Ramars;Zhong, Jun;Molina, Henrik;Chaerkady, Raghotharna;Iwahori, Akiko;Kalume, Dario Eluan;Gronborg, Mads;Joore, Jos;Cope, Leslie;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh

Identification of c-Src tyrosine kinase substrates in platelet-derived growth factor receptor signaling.