Structural and biochemical studies of the insulin and IGF1 receptors
Structural and biochemical studies of the insulin and IGF1 receptors
批准号:
10477232
负责人:
W Todd MILLER
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-01-01 至 2023-06-30
关键词:
AddressAdhesionsAffectAffinityAgonistAmino Acid SequenceAntidiabetic DrugsApplications GrantsBindingBiochemicalBiologicalCancer ModelCell Surface ReceptorsCell membraneCellsCellular Metabolic ProcessCholesterolCollaborationsCrystallizationCultured CellsCyclodextrinsCytoplasmic TailDependenceDetergentsDiabetes MellitusDimerizationDiseaseDisulfidesDown-RegulationE-CadherinERBB2 geneEpitopesExtracellular DomainFamilyFluorescenceGrowthHepatocyteHomeostasisHormone ReceptorHormonesHumanIGF1 geneIn VitroIndividualInsulinInsulin ReceptorInsulin-Like Growth Factor IInsulin-Like-Growth Factor I ReceptorKineticsKnowledgeLaboratoriesLengthLigand BindingLigandsLinkLipidsMalignant NeoplasmsMammalian CellMeasurementMembraneMembrane LipidsMethodologyMolecularMolecular ConformationMonitorMusMutagenesisNon-Insulin-Dependent Diabetes MellitusPhospholipidsPhosphorylationPhosphotransferasesPhotoaffinity LabelsPlasma ExchangePlayPolypeptide HormonesPositioning AttributePreparationPrognosisProtein Tyrosine KinaseProteinsReceptor ActivationReceptor Protein-Tyrosine KinasesReceptor SignalingRegulationResistanceRoleSignal TransductionSiteSkin CancerSpecimenSphingolipidsSterolsStructureSystemTechniquesTestingTherapeuticTherapeutic InterventionTransmembrane DomainTyrosineTyrosine Kinase DomainWestern BlottingWorkcancer cellcancer invasivenesscancer therapycell growthcell typedesigndimerexperimental studygrowth hormone regulating factorhuman diseaseinhibitorinsightinsulin regulationinsulin signalingmalignant breast neoplasmmembermetabolic abnormality assessmentmigrationnew therapeutic targetnovelnovel therapeuticsreceptorreceptor functionreceptor structure functionsingle-molecule FRETsmall moleculetumorunilamellar vesicle
中文摘要
胰岛素和胰岛素样生长因子-1 (IGF1)是密切相关的多肽激素/生长因子
英文摘要
Insulin and insulin-like growth factor-1 (IGF1) are closely related polypeptide hormones/growth factors that
regulate cell growth and metabolism. Insulin and IGF1 exert their biological effects on target cells by binding to
distinct cell surface receptors, the insulin receptor (IR) and the IGF1 receptor (IGF1R), respectively, which are
structurally related receptor tyrosine kinases. IR and IGF1R have low basal activity, which is stimulated
through ligand binding to the ectodomains, resulting in autophosphorylation of specific tyrosine residues in the
cytoplasmic tyrosine kinase domains. Aberrant signaling by IR and IGF1R is relevant to human disease:
decreased signaling of IR plays a role in non-insulin-dependent diabetes mellitus, while increased signaling of
IGF1R and IR is implicated in cancer. Despite extensive structural and biochemical studies of the separate
ectodomains and cytoplasmic domains of these receptors, a comprehensive understanding of the signal
transduction mechanism for IR and IGF1R is still lacking. To address these issues, we have produced highly
purified preparations of full-length IR and IGF1R that are detergent-soluble, functional, and responsive to their
ligands. We will use biochemical approaches and single-molecule fluorescence resonance energy transfer
(FRET) to understand the relative positioning of the tyrosine kinase domains in the unliganded, basal and
phosphorylated, activated states. These structure-function studies will be correlated with studies of the
metabolic functions of IR and the growth-promoting effects of IGF1R in cultured cells. We will also test the
hypothesis that cellular sterol and lipid composition affects transmembrane signaling by IR and IGF1R. To do
this, we will take advantage of new methodology to manipulate the composition of the plasma membrane in
living cells. Finally, we will characterize the interaction between IGF1R and a soluble fragment of E-cadherin
(sEcad) that is shed from cancer cells. Previous work showed that sEcad activates IGF1R signaling in cultured
cancer cells and in human cancer specimens, and we have shown that this is due to a direct interaction
between the proteins. We will identify binding determinants on IGF1R and on sEcad that are important for this
interaction. The sEcad-IGF1R interaction represents a novel target for therapeutic intervention. The work
proposed in this grant application will advance our knowledge of the molecular mechanisms involved in
transmembrane signaling by IR and IGF1R. This information should prove to be valuable in the design of
small-molecule agonists that act intracellularly to activate IR; such agonists would have potential use as anti-
diabetic therapeutics. In addition, from an understanding of the activation mechanism, it might be possible to
develop IR/IGF1R inhibitors to block receptor signaling in cancer cells.
期刊论文(7)
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DOI:
10.1016/j.ab.2017.08.011
发表时间:
2017-11-01
期刊:
Analytical biochemistry
影响因子:
2.9
作者:
[Delle Bovi RJ, Miller WT]
通讯作者:
Miller WT
DOI:
10.7554/elife.04909
发表时间:
2014-10-28
期刊:
eLife
影响因子:
7.7
作者:
[Hubbard SR, Miller WT]
通讯作者:
Miller WT
DOI:
10.1111/cbdd.14125
发表时间:
2023-01
期刊:
Chemical biology & drug design
影响因子:
3
作者:
[]
通讯作者:
DOI:
10.1002/chem.202100990
发表时间:
2021-07-02
期刊:
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子:
--
作者:
[Tapia L, Solozabal N, Solà J, Pérez Y, Miller WT, Alfonso I]
通讯作者:
Alfonso I
Temperature sensitivities of metazoan and pre-metazoan Src kinases.
后生动物和前后生动物 Src 激酶的温度敏感性。
DOI:
10.1016/j.bbrep.2020.100775
发表时间:
2020
期刊:
Biochemistry and biophysics reports
影响因子:
2.7
作者:
[Miller,WTodd]
通讯作者:
Miller,WTodd
共 7 条
Nonreceptor tyrosine kinases in Systemic Lupus Erythematosus
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批准号:10409830
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项目类别:
-
资助金额:$31.56万
-
财政年份:2021
-
负责人:W Todd MILLER
-
依托单位:
Nonreceptor tyrosine kinases in Systemic Lupus Erythematosus
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批准号:10610475
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项目类别:
-
资助金额:$31.56万
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财政年份:2021
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负责人:W Todd MILLER
-
依托单位:
Nonreceptor tyrosine kinases in Systemic Lupus Erythematosus
-
批准号:10292827
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项目类别:
-
资助金额:$31.56万
-
财政年份:2021
-
负责人:W Todd MILLER
-
依托单位:
Structural and biochemical studies of the insulin and IGF1 receptors
-
批准号:10266022
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项目类别:
-
资助金额:$0.0万
-
财政年份:2015
-
负责人:W Todd MILLER
-
依托单位:
Structural and biochemical studies of the insulin and IGF1 receptors
-
批准号:9916628
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2015
-
负责人:W Todd MILLER
-
依托单位:
Regulation of insulin-like growth factor I receptor tyrosine kinase
-
批准号:7578946
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项目类别:
-
资助金额:$28.95万
-
财政年份:2008
-
负责人:W Todd MILLER
-
依托单位:
Regulation of insulin-like growth factor I receptor tyrosine kinase
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批准号:7364070
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项目类别:
-
资助金额:$30.43万
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财政年份:2008
-
负责人:W Todd MILLER
-
依托单位:
Regulation of insulin-like growth factor I receptor tyrosine kinase
-
批准号:7752492
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项目类别:
-
资助金额:$28.95万
-
财政年份:2008
-
负责人:W Todd MILLER
-
依托单位:
Regulation of insulin-like growth factor I receptor tyrosine kinase
-
批准号:7995988
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项目类别:
-
资助金额:$28.08万
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财政年份:2008
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负责人:W Todd MILLER
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依托单位:
PURCHASE OF A HIGH SENSITIVITY PROTEIN SEQUENCER
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批准号:2487488
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项目类别:
-
资助金额:$13.28万
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财政年份:1998
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负责人:W Todd MILLER
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依托单位:
SUBSTRATE SPECIFICITY OF NONRECEPTOR TYROSINE KINASES
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批准号:2099215
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项目类别:
-
资助金额:$9.77万
-
财政年份:1993
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负责人:W Todd MILLER
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依托单位:
Substrate specificity of nonreceptor tyrosine kinases
-
批准号:7849943
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项目类别:
-
资助金额:$22.08万
-
财政年份:1993
-
负责人:W Todd MILLER
-
依托单位:
Substrate specificity of nonreceptor tyrosine kinases
-
批准号:7002226
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项目类别:
-
资助金额:$20.94万
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财政年份:1993
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负责人:W Todd MILLER
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依托单位:
SUSTRATE SPECIFICITY OF NONRECEPTOR TYROSINE KINASE
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批准号:6512894
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项目类别:
-
资助金额:$17.18万
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财政年份:1993
-
负责人:W Todd MILLER
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依托单位:
SUSTRATE SPECIFICITY OF NONRECEPTOR TYROSINE KINASE
-
批准号:6362576
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项目类别:
-
资助金额:$16.68万
-
财政年份:1993
-
负责人:W Todd MILLER
-
依托单位:
Substrate specificity of nonreceptor tyrosine kinases
-
批准号:6729461
-
项目类别:
-
资助金额:$21.45万
-
财政年份:1993
-
负责人:W Todd MILLER
-
依托单位:
Substrate specificity of nonreceptor tyrosine kinases
-
批准号:8193182
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项目类别:
-
资助金额:$20.8万
-
财政年份:1993
-
负责人:W Todd MILLER
-
依托单位:
SUSTRATE SPECIFICITY OF NONRECEPTOR TYROSINE KINASE
-
批准号:6164083
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项目类别:
-
资助金额:$18.8万
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财政年份:1993
-
负责人:W Todd MILLER
-
依托单位:
SUBSTRATE SPECIFICITY OF NONRECEPTOR TYROSINE KINASES
-
批准号:2099217
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项目类别:
-
资助金额:$10.68万
-
财政年份:1993
-
负责人:W Todd MILLER
-
依托单位:
Substrate specificity of nonreceptor tyrosine kinases
-
批准号:7169217
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项目类别:
-
资助金额:$20.34万
-
财政年份:1993
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负责人:W Todd MILLER
-
依托单位:
海外基金