GPCR - Linked RhoGEFs in Tumor Growth and Metastasis
GPCR - Linked RhoGEFs in Tumor Growth and Metastasis
批准号:
10338123
负责人:
John Tesmer
金额:
$34.86万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-03-01 至 2024-02-29
关键词:
Binding SitesBiologicalBiological AssayCRISPR/Cas technologyCancer Cell GrowthCancer PatientCatalytic DomainCell ProliferationCell modelCell physiologyCellsCellular biologyChemotaxisCollaborationsComplexCryoelectron MicroscopyCrystallizationDeuteriumDevelopmentEnzymesFamilyG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding ProteinsGoalsGrowthGuanine Nucleotide Exchange FactorsHeterotrimeric GTP-Binding ProteinsHomeostasisHormonesHumanHydrogenIn VitroLeadLightLinkLipidsMalignant NeoplasmsMammary NeoplasmsMass Spectrum AnalysisMetastatic breast cancerMolecularMutationNMR SpectroscopyNeoplasm MetastasisOcular MelanomaPH DomainPathologicPathway interactionsPeptide aptamersPeptidesPhysiologicalPlayProstatic NeoplasmsRegulationRoleSignal PathwaySignal TransductionStimulusStructureSystemTestingTherapeuticVariantX-Ray Crystallographybiophysical techniquescancer cellcancer genomecell growthcombatdesignextracellulargenome editinginnovationinsightleukemialink proteinmalignant breast neoplasmmembermigrationnovel strategiesnovel therapeutic interventionoverexpressionpreventresponserhorho GTP-Binding Proteinssmall molecule inhibitorstemsynergismtumor growth
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
G protein-coupled receptors (GPCRs) are well known for their ability to convert extracellular information
encoded in hormones, odorants, and peptides into rapid changes in cellular homeostasis by modulating the
function of effector enzymes and channels in the cell. However, analysis of human cancer genomes indicates
that some GPCR signaling pathways lead to sustained signals that in pathological settings are linked to tumor
growth and metastasis. A common feature of such pathways is the activation of Rho GTPases by Dbl family
Rho guanine nucleotide exchange factors (RhoGEFs). The TrioC subfamily (composed of Trio, Kalirin, and
p63RhoGEF) is directly activated by heterotrimeric Gαq subunits and is strongly implicated in ocular melanoma
and leukemia. The P-Rex subfamily (composed of P-Rex1 and 2) is activated synergistically by direct
interactions with GBetagamma and the lipid PIP3, and is overexpressed in many breast and prostate tumors where it
plays a metastatic role. Trio and P-Rex1/2 have thus emerged as important chemotherapeutic targets. The fact
that the molecular and cellular mechanisms underlying regulation of these enzymes are as of yet poorly
understood prevents a rational approach to the design of novel therapeutic approaches. By determining
crystallographic and cryo-EM structures of members from these RhoGEF subfamilies, this proposal seeks to
define molecular mechanisms of activation and to test these hypotheses through a battery of functional assays.
In parallel, we extend our functional analysis into model cell systems to understand how constitutively active
heterotrimeric G proteins and GPCRs promote cancer cell growth (as in ocular melanoma) and metastasis (as
in breast cancer) via TrioC and P-Rex subfamily RhoGEFs. By understanding the basis for regulation of
RhoGEF activity by heterotrimeric G proteins both in vitro and in relevant cellular contexts, we will accelerate
discovery of new biological insights and novel therapeutic strategies that can be used to combat cancer.
期刊论文(9)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1016/j.str.2020.03.008
发表时间:
2020-07-07
期刊:
STRUCTURE
影响因子:
5.7
作者:
[Li, Yilai, Cash, Jennifer N., Cianfrocco, Michael A.]
通讯作者:
Cianfrocco, Michael A.
Characterization of a hyperphosphorylated variant of G protein-coupled receptor kinase 5 expressed in E. coli.
大肠杆菌中表达的 G 蛋白偶联受体激酶 5 过度磷酸化变体的表征。
DOI:
10.1016/j.pep.2019.105547
发表时间:
2020
期刊:
Protein expression and purification
影响因子:
1.6
作者:
[Beyett,TylerS, Chen,Qiuyan, Labudde,EmilyJ, Krampen,Joseph, Sharma,PrateekV, Tesmer,JohnJG]
通讯作者:
Tesmer,JohnJG
New X-ray Diffractometer and Detector for Purdue Macromolecular Crystallography
-
批准号:10431439
-
项目类别:
-
资助金额:$85.99万
-
财政年份:2022
-
负责人:John Tesmer
-
依托单位:
FASEB SRC on G Protein-Coupled Receptor Kinases and Arrestins: From Structure to Disease
-
批准号:9330648
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2017
-
负责人:John Tesmer
-
依托单位:
Structure and Function of the LPLA2/LCAT Acyltransferase Family
-
批准号:9174909
-
项目类别:
-
资助金额:$48.34万
-
财政年份:2014
-
负责人:John Tesmer
-
依托单位:
Structure and Function of the LPLA2/LCAT Acyltransferase Family
-
批准号:8817382
-
项目类别:
-
资助金额:$56.11万
-
财政年份:2014
-
负责人:John Tesmer
-
依托单位:
RNA Aptamer-Based Screen for Selective Inhibitors of GRK2
-
批准号:7929294
-
项目类别:
-
资助金额:$3.86万
-
财政年份:2010
-
负责人:John Tesmer
-
依托单位:
RNA Aptamer-Based Screen for Selective Inhibitors of GRK2
-
批准号:8063896
-
项目类别:
-
资助金额:$3.75万
-
财政年份:2010
-
负责人:John Tesmer
-
依托单位:
Molecular basis for the regulation of G protein-coupled receptor kinases
-
批准号:8281593
-
项目类别:
-
资助金额:$41.07万
-
财政年份:2009
-
负责人:John Tesmer
-
依托单位:
Molecular basis for the regulation of G protein-coupled receptor kinases
-
批准号:7906035
-
项目类别:
-
资助金额:$41.5万
-
财政年份:2009
-
负责人:John Tesmer
-
依托单位:
Phosphorylation and G Protein Signaling Networks Gordon Conferences
-
批准号:8076873
-
项目类别:
-
资助金额:$0.3万
-
财政年份:2009
-
负责人:John Tesmer
-
依托单位:
Molecular basis for the regulation of G protein-coupled receptor kinases
-
批准号:7736619
-
项目类别:
-
资助金额:$41.21万
-
财政年份:2009
-
负责人:John Tesmer
-
依托单位:
Molecular basis for the regulation of G protein-coupled receptor kinases
-
批准号:8078908
-
项目类别:
-
资助金额:$41.13万
-
财政年份:2009
-
负责人:John Tesmer
-
依托单位:
Phosphorylation and G Protein Signaling Networks Gordon Conferences
-
批准号:8332532
-
项目类别:
-
资助金额:$0.3万
-
财政年份:2009
-
负责人:John Tesmer
-
依托单位:
Structural Studies of Galphaq and Its Complexes at the Cell Membrane
-
批准号:7339834
-
项目类别:
-
资助金额:$36.96万
-
财政年份:2007
-
负责人:John Tesmer
-
依托单位:
Structural Studies of Galphaq and Its Complexes at the Cell Membrane
-
批准号:7186054
-
项目类别:
-
资助金额:$35.4万
-
财政年份:2007
-
负责人:John Tesmer
-
依托单位:
Structural and Functional Studies of Galphaq and Its Signaling Complexes
-
批准号:8589422
-
项目类别:
-
资助金额:$38.62万
-
财政年份:2007
-
负责人:John Tesmer
-
依托单位:
Structural Studies of Galphaq and Its Complexes at the Cell Membrane
-
批准号:7758792
-
项目类别:
-
资助金额:$36.96万
-
财政年份:2007
-
负责人:John Tesmer
-
依托单位:
Structural and Functional Studies of Galphaq and Its Signaling Complexes
-
批准号:8399040
-
项目类别:
-
资助金额:$37.51万
-
财政年份:2007
-
负责人:John Tesmer
-
依托单位:
Structural and Functional Studies of Galphaq and Its Signaling Complexes
-
批准号:8246234
-
项目类别:
-
资助金额:$41.0万
-
财政年份:2007
-
负责人:John Tesmer
-
依托单位:
Structural Studies of Galphaq and Its Complexes at the Cell Membrane
-
批准号:7545541
-
项目类别:
-
资助金额:$36.96万
-
财政年份:2007
-
负责人:John Tesmer
-
依托单位:
Structure, function, and inhibition of G protein-coupled receptor kinases
-
批准号:10397582
-
项目类别:
-
资助金额:$60.05万
-
财政年份:2004
-
负责人:John Tesmer
-
依托单位:
海外基金