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：
8583092
负责人：
Subramaniam Malarkannan
金额：
$ 37.21万
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583092
关键词：
Actins Activities of Daily Living Binding Cell Size Cell division Cell physiology Complex Cytolysis Cytoplasmic Granules Cytoskeletal Modeling Development Distal Event Genetic Transcription IL2RB gene Immunology Immunotherapy 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 neuronal cell body novel promoter public health relevance 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 ?-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）：淋巴细胞中信号事件的时空组织知之甚少。配体通过独特的受体启动多个信号通路。数百个信号分子参与将复杂的膜近端事件转化为有意义的细胞功能。尽管在理解信号分子方面取得了出色的进步，但协调这些因素的确切机制仍然是一个谜。脚手架蛋白提供了一部分解释，即信号事件如何在空间时秒。 IQGAP1是190 kDa的细胞质脚手架蛋白。在此应用程序中，我们建议确定特定信号事件的时空相对性如何由IQGAP1控制。我们假设IQGAP1充当处理中心，以协调多个信号通路。通过初步工作，我们确定了IQGAP1的三个主要脚手架功能。首先，IQGAP1调节？-Catenin/TCF/LEF激活途径，与NK细胞的末端成熟和子集规范有关。其次，IQGAP1围绕核周围区域形成一个新型的信号体，以通过Rac1-> Pak-> Raf-> Mek1/2途径来调节ERK1/2激活。第三，IQGAP1在肌动蛋白聚合，微管伸长和MTOC形成中起着核心作用，这对于免疫突触形成，肿瘤裂解和细胞运动很重要。在此应用中，我们建议确定IQGAP1介导这些脚手架功能的确切机制。