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Signalling Processes in Dictyostelium

盘基网柄菌的信号传导过程

基本信息

批准号：
8812867
负责人：
RICHARD A FIRTEL
金额：
$ 52.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-07-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812867
关键词：
Adenylate Cyclase Bacterial Infections Behavior Binding Biochemical Biological Biological Process Cell surface Cells Chemicals Chemotactic Factors Chemotaxis Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoskeleton Development Dictyostelium Eukaryota Event F-Actin Family Feedback Food Future G-Protein-Coupled Receptors Genetic Glycogen Synthase Kinase 3 Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Human Individual Infection LRRK2 gene Lateral Leukocytes Light Link Mammalian Cell Mammary Neoplasms Mediating Molecular Morphogenesis Motor Movement Myosin Type II Natural Immunity Neoplasm Metastasis Null Lymphocytes Parkinson Disease Pathway interactions Phosphotransferases Play Population Process Protein Kinase Proteins Receptor Protein-Tyrosine Kinases Regulation Regulatory Pathway Research Role Series Side Signal Pathway Signal Transduction Sirolimus Site Source System Time Work Wound Healing autocrine base biochemical tools cancer cell cell motility cell type crosslink extracellular filamin human disease in vivo insight link protein macrophage member migration neoplastic cell neutrophil novel paracrine polarized cell polymerization protein crosslink response signal processing social tissue repair

项目摘要

DESCRIPTION (provided by applicant): Chemotaxis, or directional movement of cells up a chemical gradient, plays important roles in a wide range of cellular behaviors. Naive, randomly moving cells, such as leukocytes and Dictyostelium cells must be able to directionally sense extremely shallow extracellular chemoattractant gradients and respond by establishing a polarized cytoskeleton with an F-actin-based protruding pseudopod or lamellipod at the leading edge and a contractile trailing edge. This polarization is achieved through the spatially restricted amplification of the external gradient through the localized activation of pathways at the site of the cortex closest to the chemoattractant source. While significant advancements have been made in identifying many components that control chemotaxis, we do not yet understand how cells sense the direction of the gradient and restrict responses to the leading edge, how newly polymerized F-actin networks are stabilized to form pseudopod, or what regulates the timing of these events. Furthermore, chemotaxing cells are able to communicate, within the cell population, to organize more global social responses, such as the autocrine aggregation response in Dictyostelium cells in which cells respond to and then secrete the chemoattractant cAMP leading to the coordinate aggregation of ~105 cells (signal relay) or the paracrine response system used by macrophages and mammary tumor cells, resulting in interdependent migration of the two cell types during metastasis. As many of the pathways are evolutionarily conserved, we will use Dictyostelium to achieve three important goals: 1) We have demonstrated that TORC2, through the activation of PKB and PKBR1, integrates multiple inputs to regulate chemotaxis by controlling directional sensing and F-actin polymerization, and to control signal relay through the regulation of adenylyl cyclase. Furthermore, we have found that cAMP, through the activation of PKA, acts as an important feedback loop to negatively regulate the TORC2/PKB:PKBR1 pathway. We will investigate the molecular basis of this key feedback loop. 2) We have found that GSK-3 is an important regulator of chemotaxis and by comparing the phosphoproteomes of wild-type and GSK-3 null cells have identified putative GSK-3 substrates, including known components of the Ras/Rap1/F-actin pathways that control chemotaxis. Our goal is to define key GSK- 3 substrates and understand how GSK-3 functions to control chemotaxis. 3) We have identified a novel regulatory pathway that plays a central role in forming and stabilizing the pseudopod during chemotaxis. We have shown that Rab1A binds to and is required to activate Roco2, a member of the Roco family of GTPase-containing protein kinases. Roco2 acts upstream of the F-actin cross- linking protein filamin and both are required for pseudopod extension. We will examine the mechanism by which this pathway is regulated and how it controls chemotaxis.

描述（由申请人提供）：趋化性，或细胞沿化学梯度的定向运动，在广泛的细胞行为中起重要作用。幼稚的，随机移动的细胞，如白细胞和Dictyosteoprotein细胞必须能够定向感测极浅的细胞外化学引诱物梯度，并通过建立一个极化的细胞骨架与F-肌动蛋白为基础的突出伪足或片足的前缘和收缩后缘。这种极化是通过在最接近化学引诱物来源的皮质部位局部激活途径，通过外部梯度的空间限制性放大来实现的。虽然在确定控制趋化性的许多组分方面取得了重大进展，但我们还不了解细胞如何感知梯度的方向并将反应限制在前沿，新聚合的F-肌动蛋白网络如何稳定以形成伪足，或者是什么调节了这些事件的时间。此外，趋化细胞能够在细胞群体内进行通信，以组织更多的全局社会反应，例如网骨藻细胞中的自分泌聚集反应，其中细胞响应并随后分泌化学引诱物cAMP，导致约105个细胞的协调聚集（信号中继）或巨噬细胞和乳腺肿瘤细胞使用的旁分泌反应系统，导致转移期间两种细胞类型的相互依赖的迁移。由于许多途径在进化上是保守的，我们将使用网骨藻来实现三个重要目标：1）我们已经证明，TORC 2通过激活PKB和PKBR 1，整合多个输入，通过控制定向传感和F-肌动蛋白聚合来调节趋化性，并通过调节腺苷酸环化酶来控制信号中继。此外，我们发现cAMP通过PKA的激活，作为一个重要的反馈回路，负调控TORC 2/PKB：PKBR 1通路。我们将研究这个关键反馈回路的分子基础。 2)我们发现GSK-3是一个重要的趋化调节因子，通过比较野生型和GSK-3空细胞的磷酸化蛋白质组，已经确定了推定的GSK-3底物，包括控制趋化性的Ras/Rap 1/F-actin途径的已知组分。我们的目标是定义关键的GSK- 3底物，并了解GSK-3如何控制趋化性。 3)我们已经确定了一种新的调控途径，在形成和稳定的伪足在趋化性中发挥着核心作用。我们已经表明，Rab 1A结合，并需要激活Roco 2，一个成员的Roco家族的GTP酶的蛋白激酶。Roco 2在F-肌动蛋白交联蛋白细丝蛋白的上游起作用，并且两者都是伪足延伸所需的。我们将研究这一途径的调节机制，以及它如何控制趋化性。

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dictyostelium Dock180-related RacGEFs regulate the actin cytoskeleton during cell motility.

盘基网柄菌 Dock180 相关的 RacGEF 在细胞运动过程中调节肌动蛋白细胞骨架。

DOI：
10.1091/mbc.e08-09-0899
发表时间：
2009
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Para,Alessia;Krischke,Miriam;Merlot,Sylvain;Shen,Zhouxin;Oberholzer,Michael;Lee,Susan;Briggs,Steven;Firtel,RichardA
通讯作者：
Firtel,RichardA

Cooperative cell motility during tandem locomotion of amoeboid cells.

DOI：
10.1091/mbc.e15-12-0836
发表时间：
2016-04-15
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Bastounis E;Álvarez-González B;del Álamo JC;Lasheras JC;Firtel RA
通讯作者：
Firtel RA

Incoherent feedforward control governs adaptation of activated ras in a eukaryotic chemotaxis pathway.

DOI：
10.1126/scisignal.2002413
发表时间：
2012-01-03
期刊：
Science signaling
影响因子：
7.3
作者：
Takeda K;Shao D;Adler M;Charest PG;Loomis WF;Levine H;Groisman A;Rappel WJ;Firtel RA
通讯作者：
Firtel RA

A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration.

DOI：
10.1016/j.devcel.2010.03.017
发表时间：
2010-05-18
期刊：
DEVELOPMENTAL CELL
影响因子：
11.8
作者：
Charest, Pascale G.;Shen, Zhouxin;Lakoduk, Ashley;Sasaki, Atsuo T.;Briggs, Steven P.;Firtel, Richard A.
通讯作者：
Firtel, Richard A.

The SCAR/WAVE complex is necessary for proper regulation of traction stresses during amoeboid motility.

疤痕/波复合物对于在变形虫运动过程中适当调节牵引力是必要的。