Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2

SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用

基本信息

  • 批准号:
    8795270
  • 负责人:
  • 金额:
    $ 5.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-05-01 至 2015-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The ubiquitously expressed adaptor protein Grb2 is crucial for the activation and propagation of signaling pathways that control many human physiological processes. Along with its role in propagating signaling pathways downstream of activated receptors and adaptor proteins, the disregulated formation of Grb2-mediated complexes has been linked to numerous pathological conditions in humans, including cancer, diabetes, autoimmune disorders, allergies/asthma and cardiovascular disease. Grb2 is composed of a Src homology 2 (SH2) domain, which binds specific phosphorylated tyrosines, flanked by two Src homology 3 (SH3) domains, which associate with proline- rich sequences. The interaction of Grb2 with SH2 and SH3 domain ligands has been extensively examined. Because of this, Grb2 is the primary model system for our understanding of the activation and function of SH and SH3 domain-containing proteins. Although these studies have provided insight into potential ligands and the binding mechanism of Grb2 and other important signaling proteins, they have not clearly addressed several critical questions. An examination of these questions is important if we are to fully understand how Grb2 and other related proteins regulate the formation and function of clinically relevant complexes. Our long-term goal is to characterize how SH2 and SH3 domain- containing proteins control the formation and function of clinically relevant signaling complexes in order to facilitate the develop of therapeutic regimens for diseases linked to the disregulated formation of these complexes. The objective of this specific proposal is to comprehensively examine the Grb2- mediated complexes that form at an SH2 domain ligand, the adaptor protein LAT. Our central working hypothesis is that Grb2 forms cooperative interactions with both LAT and individual SH3 domain ligands that control the formation and function of these critical multiprotein signaling complexes. To test this hypothesis, we will 1) molecularly characterize the interaction of Grb2 with the SH3 domain ligands Sos1, HPK1 and c-Cbl, 2) determine the forces that drive the association of specific Grb2 SH3 domain ligands with LAT and 3) determine the role of SH3 domain ligands in the interaction of Grb2 with LAT. To achieve these aims, we will employ several innovative, state-of-the-art biophysical, and biochemical techniques, including our new, more robust analysis methods for isothermal titration calorimetry and sedimentation velocity analytical ultracentrifugation. The information gained from these studies will allow us to significantly advance our understanding of the binding mechanism of Grb2 and other related proteins to both SH2 and SH3 domains ligands. This will not only provide new insight into the formation of SH2 and SH3 domain-mediated signaling complexes, but will also facilitate the production and/or use of novel therapeutic agents for the treatment of debilitating human diseases.
描述(由申请人提供):普遍表达的衔接蛋白 Grb2 对于控制许多人类生理过程的信号通路的激活和传播至关重要。除了其在传播激活受体和衔接蛋白下游信号通路中的作用之外,Grb2介导的复合物形成失调与人类的许多病理状况有关,包括癌症、糖尿病、自身免疫性疾病、过敏/哮喘和心血管疾病。 Grb2 由一个 Src 同源 2 (SH2) 结构域组成,该结构域结合特定的磷酸化酪氨酸,两侧是两个 Src 同源 3 (SH3) 结构域,与富含脯氨酸的序列相关。 Grb2 与 SH2 和 SH3 结构域配体的相互作用已被广泛研究。因此,Grb2 是我们了解含有 SH 和 SH3 结构域的蛋白质的激活和功能的主要模型系统。尽管这些研究深入了解了潜在的配体以及 Grb2 和其他重要信号蛋白的结合机制,但它们尚未明确解决几个关键问题。如果我们要充分了解 Grb2 和其他相关蛋白如何调节临床相关复合物的形成和功能,对这些问题的研究非常重要。我们的长期目标是表征包含 SH2 和 SH3 结构域的蛋白质如何控制临床相关信号复合物的形成和功能,以促进与这些复合物形成失调相关的疾病的治疗方案的开发。该具体提案的目的是全面检查在 SH2 结构域配体(接头蛋白 LAT)上形成的 Grb2 介导的复合物。我们的中心工作假设是 Grb2 与 LAT 和单个 SH3 结构域配体形成协同相互作用,控制这些关键多蛋白信号复合物的形成和功能。为了检验这一假设,我们将 1) 从分子角度表征 Grb2 与 SH3 结构域配体 Sos1、HPK1 和 c-Cbl 的相互作用,2) 确定驱动特定 Grb2 SH3 结构域配体与 LAT 结合的力,3) 确定 SH3 结构域配体在 Grb2 与 LAT 相互作用中的作用。为了实现这些目标,我们将采用多种创新、最先进的生物物理和生化技术,包括用于等温滴定量热法和沉降速度分析超速离心的新的、更强大的分析方法。从这些研究中获得的信息将使我们能够显着增进对 Grb2 和其他相关蛋白与 SH2 和 SH3 结构域配体的结合机制的理解。这不仅将为SH2和SH3结构域介导的信号复合物的形成提供新的见解,而且还将促进用于治疗使人衰弱的人类疾病的新型治疗剂的生产和/或使用。

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)
Activated PLC-γ1 is catalytically induced at LAT but activated PLC-γ1 is localized at both LAT- and TCR-containing complexes.
  • DOI:
    10.1016/j.cellsig.2013.12.022
  • 发表时间:
    2014-04
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Cruz-Orcutt N;Vacaflores A;Connolly SF;Bunnell SC;Houtman JC
  • 通讯作者:
    Houtman JC
The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation.
TCR-mediated functions are enhanced in activated peripheral blood T cells isolated from leucocyte reduction systems.
从白细胞减少系统中分离出的活化外周血 T 细胞的 TCR 介导功能得到增强。
  • DOI:
    10.1016/j.jim.2014.11.009
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    2.2
  • 作者:
    Tremblay,MikaelaM;Houtman,JonCD
  • 通讯作者:
    Houtman,JonCD
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Jon C.D. Houtman其他文献

Comparative study of bacterial SPOR domains identifies functionally important differences in glycan binding affinity
细菌 SPOR 结构域的比较研究确定了聚糖结合亲和力的重要功能差异
  • DOI:
    10.1101/2022.07.01.498525
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Atsushi Yahashiri;Gabriela M. Kaus;D. Popham;Jon C.D. Houtman;David S. Weiss
  • 通讯作者:
    David S. Weiss

Jon C.D. Houtman的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Jon C.D. Houtman', 18)}}的其他基金

R25 YES: Cancer Research Opportunities at Iowa
R25 是:爱荷华州的癌症研究机会
  • 批准号:
    10712349
  • 财政年份:
    2023
  • 资助金额:
    $ 5.47万
  • 项目类别:
MMP-9 based immune-driven mechanisms of neovascular AMD
基于MMP-9的新生血管性AMD的免疫驱动机制
  • 批准号:
    10719958
  • 财政年份:
    2023
  • 资助金额:
    $ 5.47万
  • 项目类别:
CD4 T cell intrinsic signaling defects during viral exhaustion
病毒耗竭期间 CD4 T 细胞内在信号传导缺陷
  • 批准号:
    10359809
  • 财政年份:
    2021
  • 资助金额:
    $ 5.47万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8530594
  • 财政年份:
    2010
  • 资助金额:
    $ 5.47万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8220881
  • 财政年份:
    2010
  • 资助金额:
    $ 5.47万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8606956
  • 财政年份:
    2010
  • 资助金额:
    $ 5.47万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8610251
  • 财政年份:
    2010
  • 资助金额:
    $ 5.47万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    7883144
  • 财政年份:
    2010
  • 资助金额:
    $ 5.47万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8068032
  • 财政年份:
    2010
  • 资助金额:
    $ 5.47万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8447598
  • 财政年份:
    2010
  • 资助金额:
    $ 5.47万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 5.47万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了