Molecular mechanisms of signaling co-ordination in innate lymphocytes

先天淋巴细胞信号协调的分子机制

基本信息

批准号：
9097517
负责人：
Subramaniam Malarkannan
金额：
$ 38.69万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-09 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097517
关键词：
Actins Activities of Daily Living Binding Cell Size Cell division Cell physiology Cells Complex Cytolysis Cytoplasmic Granules Cytoskeletal Modeling Development Distal Event Genetic Transcription Health IL2RB gene Immunology Immunotherapy KSR gene Kinetics Knock-out Ligands Link Lymphocyte MAP2K1 gene MAPK3 gene Mediating Membrane Microtubule Polymerization Microtubule-Organizing Center Molecular Movement Mus NK Cell Activation Natural Killer Cells Outcome Study Pathway interactions Phosphorylation Phosphotransferases Play Process Production Regulation Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Molecule Site Testing Transcriptional Activation Tubulin Work cell motility chemokine cytokine cytotoxic cytotoxicity immunological synapse formation in vivo insight novel promoter receptor reconstitution scaffold spatiotemporal transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Spatiotemporal organization of signaling events in lymphocytes are poorly understood. Ligands initiate multiple signaling pathways via unique receptors. Hundreds of signaling molecules take part in transducing complex membrane proximal events into meaningful cellular functions. Although exceptional progress has been made in the understanding of signaling molecules, the precise mechanisms that co-ordinate these factors remain an enigma. Scaffolding proteins have provided part of the explanation into how signaling events can be spatiotemporally coordinated. IQGAP1 is a 190 kDa cytoplasmic scaffolding protein. In this application, we propose to determine how the spacetime relativity of specific signaling events is controlled by IQGAP1. We hypothesize that IQGAP1 functions as a processing center to coordinate multiple signaling pathways. Through our preliminary work, we identify three major scaffolding functions for IQGAP1. First, IQGAP1 regulates ß-catenin/TCF/LEF activation pathway that is involved in the terminal maturation and subset specification of NK cells. Second, IQGAP1 forms a novel signalosome around the perinuclear region to regulate ERK1/2 activation via Rac1->Pak->Raf->MEK1/2 pathway. Third, IQGAP1 plays a central role in actin polymerization, microtubule elongation and MTOC formation, which are important for the immunological synapse formation, tumor lysis and cell movement. In this application, we propose to determine the precise mechanisms by which IQGAP1 mediates these scaffolding functions.

描述（由申请人提供）：尽管已经取得了非凡的进展，但对淋巴细胞中信号传导事件的时空组织仍知之甚少。在理解信号分子的过程中，协调这些因素的精确机制仍然是一个谜，支架蛋白为信号事件如何时空协调提供了部分解释。 IQGAP1 是一种 190 kDa 的细胞质支架蛋白。通过我们的初步工作，我们建议确定 IQGAP1 如何控制特定信号事件的时空相关性。我们确定了 IQGAP1 的三个主要支架功能，首先，IQGAP1 调节参与终末成熟和的 ß-catenin/TCF/LEF 激活途径。其次，IQGAP1 在核周区域形成一种新型信号体，通过 Rac1->Pak->Raf->MEK1/2 途径调节 ERK1/2 激活。第三，IQGAP1 在肌动蛋白聚合和微管中发挥核心作用。伸长和 MTOC 形成，这对于免疫突触形成、肿瘤裂解和细胞运动很重要。在本申请中，我们建议确定其精确机制。 IQGAP1 介导这些支架功能。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clinical relevance of natural killer cells following hematopoietic stem cell transplantation.

造血干细胞移植后自然杀伤细胞的临床相关性。

DOI：
发表时间：
2013
期刊：
影响因子：
3.9
作者：
Palmer, Jeanne M;Rajasekaran, Kamalakannan;Thakar, Monica S;Malarkannan, Subramaniam
通讯作者：
Malarkannan, Subramaniam

IL-22: An Evolutionary Missing-Link Authenticating the Role of the Immune System in Tissue Regeneration.

IL-22：验证免疫系统在组织再生中的作用的进化缺失环节。

DOI：
发表时间：
2013
期刊：
影响因子：
3.9
作者：
Kumar, Pawan;Rajasekaran, Kamalakannan;Palmer, Jeanne M;Thakar, Monica S;Malarkannan, Subramaniam
通讯作者：
Malarkannan, Subramaniam

mTORC1 and mTORC2 differentially promote natural killer cell development.

mTORC1 和 mTORC2 不同程度地促进自然杀伤细胞发育。

DOI：
发表时间：
2018
期刊：
影响因子：
7.7
作者：
Yang, Chao;Tsaih, Shirng;Lemke, Angela;Flister, Michael J;Thakar, Monica S;Malarkannan, Subramaniam
通讯作者：
Malarkannan, Subramaniam