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Diacylglycerol Kinase Delta in Growth and Development

二酰甘油激酶 Delta 在生长和发育中的作用

基本信息

批准号：
8109244
负责人：
MATTHEW KENT TOPHAM
金额：
$ 26.14万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-25 至 2013-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) regulates proliferation, migration, apoptosis, and differentiation of cells. Many types of cancer have abnormally high EGFR activity that contributes to their growth, and studies have shown that inhibiting EGFR can reduce tumor size. We made diacylglycerol kinase (DGK) delta knockout mice and discovered that by regulating protein kinase C enzymes, DGKdelta modulates the expression and activity of EGFR. This proposal has three aims that will help us understand how DGKdelta regulates EGFR signaling and will test the potential anti-tumor effects of disrupting the function of DGKdelta. In Aim 1, we will determine how DGKdelta modulates EGFR expression. We found enhanced EGFR ubiquitination and increased PKC activity in DGKdelta deficient cells. Additionally, we discovered that PKCalpha is required for proper EGFR ubiquitination. Together, these data led us to hypothesize that DGKdelta regulates EGFR ubiquitination through PKCalpha. We will test this possibility in Aim 1. We also discovered that DGKdelta modulates EGFR activity independently of changes in EGFR expression. In DGKdelta deficient cells and tissues, we found enhanced phosphorylation of a threonine residue in EGFR. This phosphorylation is known to inhibit EGFR activity and our data indicate that PKCdelta is responsible. This led us to hypothesize that DGKdelta regulates EGFR activity by inhibiting PKCdelta phosphorylation of EGFR. In Aim 2, we will test this possibility. Finally, in Aim 3, we will use cell culture and mouse xenograft models to test the impact on tumorigenesis of disrupting the function of DGKdelta. Collectively, our experiments will clarify how DGKdelta regulates EGFR signaling, will define the contribution of DGKdelta to tumor formation, and will measure the anti-tumor effects of disrupting the function of DGKdelta. PUBLIC HEALTH RELEVANCE: EGFR is an important cancer target. We have found a novel way to regulate its expression and activity. These properties of EGFR are fundamentally important for it to promote cancer and our experiments might uncover new anti-cancer therapies. Thus, our proposal has important relevance to public health.

描述（由申请人提供）：表皮生长因子受体（EGFR）调节细胞的增殖、迁移、凋亡和分化。许多类型的癌症具有异常高的EGFR活性，这有助于它们的生长，研究表明抑制EGFR可以减小肿瘤大小。我们制造了二酰基甘油激酶（DGK）δ敲除小鼠，并发现通过调节蛋白激酶C酶，DGK δ调节EGFR的表达和活性。该提案有三个目标，将帮助我们了解DGKdelta如何调节EGFR信号传导，并将测试破坏DGKdelta功能的潜在抗肿瘤作用。在目标1中，我们将确定DGKdelta如何调节EGFR表达。我们发现DGKdelta缺陷细胞中EGFR泛素化增强和PKC活性增加。此外，我们发现PKCalpha是EGFR泛素化所必需的。总之，这些数据使我们假设DGKdelta通过PKCalpha调节EGFR泛素化。我们将在目标1中测试这种可能性。我们还发现，DGKdelta调节EGFR活性独立于EGFR表达的变化。在DGKdelta缺陷的细胞和组织中，我们发现EGFR中苏氨酸残基的磷酸化增强。已知这种磷酸化抑制EGFR活性，我们的数据表明PKC δ是负责的。这使我们假设DGKdelta通过抑制EGFR的PKC delta磷酸化来调节EGFR活性。在目标2中，我们将测试这种可能性。最后，在目标3中，我们将使用细胞培养和小鼠异种移植模型来测试破坏DGKdelta功能对肿瘤发生的影响。总的来说，我们的实验将阐明DGKdelta如何调节EGFR信号传导，将定义DGKdelta对肿瘤形成的贡献，并将测量破坏DGKdelta功能的抗肿瘤作用。公共卫生相关性：EGFR是一个重要的癌症靶点。我们已经找到了一种新的方法来调节其表达和活性。EGFR的这些特性对于它促进癌症具有根本重要性，我们的实验可能会发现新的抗癌疗法。因此，我们的建议对公共卫生具有重要意义。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular species of phosphatidylinositol-cycle intermediates in the endoplasmic reticulum and plasma membrane.

DOI：
10.1021/bi901551e
发表时间：
2010-01-19
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Shulga, Yulia V.;Myers, David S.;Ivanova, Pavlina T.;Milne, Stephen B.;Brown, H. Alex;Topham, Matthew K.;Epand, Richard M.
通讯作者：
Epand, Richard M.

Endocannabinoids and diacylglycerol kinase activity.

DOI：
10.1016/j.bbamem.2010.12.022
发表时间：
2011-04
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
影响因子：
3.4
作者：
Gantayet, Arpita;Jegatheswaran, Januvi;Jayakumaran, Gowtham;Topham, Matthew K.;Epand, Richard M.
通讯作者：
Epand, Richard M.

Diacylglycerol kinases as sources of phosphatidic acid.

DOI：
10.1016/j.bbalip.2009.02.010
发表时间：
2009-09
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Cai J;Abramovici H;Gee SH;Topham MK
通讯作者：
Topham MK

Study of arachidonoyl specificity in two enzymes of the PI cycle.

DOI：
10.1016/j.jmb.2011.03.071
发表时间：
2011-06-03
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Shulga YV;Topham MK;Epand RM
通讯作者：
Epand RM

Dramatic differences in the roles in lipid metabolism of two isoforms of diacylglycerol kinase.

DOI：
10.1021/bi800492c
发表时间：
2008-09-09
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Milne, Stephen B.;Ivanova, Pavlina T.;Armstrong, Michelle D.;Myers, David S.;Lubarda, Jovana;Shulga, Yulia V.;Topham, Matthew K.;Brown, H. Alex;Epand, Richard M.
通讯作者：
Epand, Richard M.