Protein phosphorylation and growth factor function

蛋白质磷酸化和生长因子功能

基本信息

批准号：
10656494
负责人：
JOAN HELLER BROWN
金额：
$ 35.15万
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：
1994
资助国家：
美国
起止时间：
1994-08-01 至 2025-06-30
项目状态：
未结题

项目摘要

Project Summary/Abstract The emerging Hippo pathway plays a major role in development, cell growth, tissue homeostasis, and organ size. Dysregulation of Hippo pathway contributes to human diseases, most notably cancer. TCGA study with analysis of over nine thousand human tumor samples has revealed that Hippo is one of the nine signals pathways that are frequently altered and contributes to human cancer. The Hippo pathway consists a kinase cascade that phosphorylates and inhibits the downstream transcription module of YAP/TAZ. A wide range of signals have been discovered to modulate the Hippo pathway. However, the precise mechanism of Hippo pathway regulation, particularly how upstream signals feed into the Hippo kinase cascade, is largely unknown. The major goal of this proposal is to understand the fundamental mechanism of Hippo pathway regulation. By screening for natural compounds to modulate the Hippo pathway, we have discovered that microcolin B (MCB) potently activates the Hippo kinases. Our preliminary study indicates that MCB directly targets phosphatidylinositol transfer protein (PITP) to activate the Hippo pathway. PITP functions to transfer phosphatidylinositol from ER, the site of synthesis, to other compartment membranes, particularly plasma membrane, in the cell. Our preliminary data suggest an exciting and novel model that phosphatidylinositol metabolites play a key role in Hippo regulation. We further propose that NF2, which is a key upstream regulator of the Hippo pathway and can bind phosphatidylinositol phosphates (PIPs), may mediate the PIP signal to Hippo regulation. This proposal aims to demonstrate the function and mechanism of phosphatidylinositol and its metabolites in Hippo regulation and how PIPs mediate upstream signals to Hippo. Further, completion of this project will provide exciting scientific basis of using small molecules to target the Hippo pathway for YAP dependent cancer.

项目摘要/摘要新兴的河马途径在发育，细胞生长，组织稳态和器官尺寸。河马途径失调会导致人类疾病，最著名的是癌症。 TCGA研究通过分析超过九千人的人类肿瘤样品，表明河马是九个信号之一经常改变并导致人类癌症的途径。河马途径包括激酶级联磷酸化并抑制YAP/TAZ的下游转录模块。广泛的已经发现信号调节河马途径。但是，河马的确切机制途径调节，尤其是上游信号如何进食河马激酶级联反应，这在很大程度上是未知的。该提案的主要目标是了解河马途径调节的基本机制。经过筛选天然化合物以调节河马途径，我们发现Microcolin B（MCB）有力激活河马激酶。我们的初步研究表明MCB直接针对磷脂酰肌醇转移蛋白（PITP）激活河马途径。 PITP功能转移磷脂酰肌醇从ER（合成位点）到其他腔室膜，尤其是等离子体膜，在细胞中。我们的初步数据提出了一个令人兴奋的新型模型，即磷脂酰肌醇代谢物在河马调节中起关键作用。我们进一步建议NF2是一个关键上游调节器河马途径并可以结合磷脂酰肌醇磷酸盐（PIPS），可以介导PIP信号到河马规定。该建议旨在证明磷脂酰肌醇及其的功能和机制河马调节中的代谢产物以及PIPS如何介导上游信号到河马。此外，完成此操作项目将提供令人兴奋的科学依据，即使用小分子以瞄准YAP的河马途径依赖癌症。

项目成果

期刊论文数量（81）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acetylation negatively regulates glycogen phosphorylase by recruiting protein phosphatase 1.

DOI：
10.1016/j.cmet.2011.12.005
发表时间：
2012-01-04
期刊：
Cell metabolism
影响因子：
29
作者：
Zhang T;Wang S;Lin Y;Xu W;Ye D;Xiong Y;Zhao S;Guan KL
通讯作者：
Guan KL

Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine.

DOI：
10.1038/s41573-020-0070-z
发表时间：
2020-07
期刊：
Nature reviews. Drug discovery
影响因子：
0
作者：
Dey A;Varelas X;Guan KL
通讯作者：
Guan KL

Regulation of the Hippo Pathway Transcription Factor TEAD.

DOI：
10.1016/j.tibs.2017.09.003
发表时间：
2017-11
期刊：
Trends in biochemical sciences
影响因子：
13.8
作者：
Lin KC;Park HW;Guan KL
通讯作者：
Guan KL

Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth.

DOI：
10.1158/0008-5472.can-16-1597
发表时间：
2016-12-01
期刊：
Cancer research
影响因子：
11.2
作者：
Lin HP;Cheng ZL;He RY;Song L;Tian MX;Zhou LS;Groh BS;Liu WR;Ji MB;Ding C;Shi YH;Guan KL;Ye D;Xiong Y
通讯作者：
Xiong Y

Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation.