LIM domain kinases: regulation and substrate recognition
LIM 结构域激酶:调节和底物识别
基本信息
- 批准号:10798525
- 负责人:
- 金额:$ 9.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:ActinsAdaptor Signaling ProteinArchitectureAreaBindingBinding ProteinsBiochemicalBiophysicsCDC42 geneCellsCellular MorphologyComplexCoupledCuesCytoskeletonDataDevelopmentEnzymesEukaryotic CellFamilyGuanosine Triphosphate PhosphohydrolasesHomeostasisLIM DomainLIM Domain Kinase 1LIMK1 geneLaboratoriesMediatingMicrofilamentsModelingMolecularMovementMyotonic DystrophyPhosphorylationPhosphotransferasesProcessProtein KinaseProteinsRegulationSignal PathwaySignal TransductionSpecificitySurfaceX-Ray Crystallographyactin depolymerizing factorcell growth regulationcofilinextracellularmolecular dynamicsp21 activated kinaserecruitrho GTP-Binding Proteinsupstream kinase
项目摘要
Multi-PI: Titus J. Boggon and Benjamin E. Turk
LIM Domain Kinases: Regulation and Substrate Recognition
ABSTRACT
Eukaryotic cells interpret extracellular and intrinsic cues to effect remodeling of the actin cytoskeleton, a process
critical for controlling cell morphology, movement, and invasiveness. Tight control of signaling pathways
impinging on the cytoskeleton is therefore essential to normal development and homeostasis. The RHO family
GTPases RHO, RAC and CDC42 each directly activate kinases (RHO kinases, PAKs, and MRCKs) in a spatially
restricted manner that in turn directly phosphorylate and activate the LIM domain kinases (LIMK1 and LIMK2).
These kinase signaling cascades ultimately converge on phosphorylation of the cofilin/ADF (actin-
depolymerizing factor) group of proteins, key molecules that mediate remodeling of actin filaments. Over the
previous two periods we have leveraged the highly complementary expertise of our two laboratories to provide
significant advances in two main areas: understanding the specificity and regulation of p21-activated kinases
(PAKs) and revealing the basis for selective targeting of cofilin by LIMKs. We will now target our efforts toward
answering outstanding questions that remain regarding regulation and function of LIMKs. Our preliminary data
suggest that an intramolecular interaction between a LIM-PDZ module and the kinase domain, potentially
involving evolutionarily conserved binding surfaces, is responsible for suppressing LIMK catalytic activity.
Combining biophysical, biochemical, and cell-based approaches, we will address the hypothesis that disruption
of this interaction results in activation of the LIM kinases, and we will reveal the structural basis for LIMK
autoregulation. We will further investigate recent evidence that LIMKs can phosphorylate both Ser and Tyr
residues by X-ray crystallography of LIMK-substrate complexes and molecular dynamics simulations. In this way
LIMKs will serve as a general model for understanding substrate recognition by the various “dual specificity”
kinase families. Finally, we will investigate the myotonic dystrophy related CDC42-binding protein kinases
(MRCKs), a major group of LIMK activating kinases downstream of the GTPase CDC42, about which little is
currently known. We will use structural, biophysical and biochemical approaches to define the basic architecture
of MRCKβ studies and to probe how its activation is coupled to interactions with LIMKs through substrate adaptor
proteins. Overall, our studies will provide a substantial advance in our molecular level understanding of signaling
pathways downstream of the RHO family GTPases that impinge on regulation of the actin cytoskeleton.
Multi-Pi:Titus J. Boggon和Benjamin E. Turk
LIM域激酶:调节和底物识别
抽象的
真核细胞解释细胞外和内在提示以实现肌动蛋白细胞骨架的重塑,这是一种过程
控制细胞形态,运动和侵入性至关重要。信号通路的严格控制
因此,撞击细胞骨架对于正常发育和稳态至关重要。 Rho家族
GTPASE RHO,RAC和CDC42各自直接激活激酶(Rho激酶,PAKS和MRCKS)
限制了直接磷酸化并激活LIM结构域激酶(Limk1和Limk2)的限制方式。
这些激酶信号传导级联对于Cofilin/adf的磷酸化最终(肌动蛋白 -
解聚因子)蛋白质组,介导肌动蛋白丝的重塑的关键分子。在
前两个时期,我们利用了两个实验室的高度完善专业知识来提供
在两个主要领域的重大进展:了解P21激活激酶的特异性和调节
(paks)并揭示了通过四肢选择性靶向cofilin的基础。现在,我们将把我们的努力定向
回答有关肢体的调节和功能仍然存在的杰出问题。我们的初步数据
表明LIM-PDZ模块与激酶结构域之间的分子内相互作用,可能有可能
涉及进化保守的结合表面,负责抑制limk催化活性。
结合生物物理,生化和基于细胞的方法,我们将解决破坏的假设
这种相互作用导致LIM激酶的激活,我们将揭示肢体的结构基础
自动调节。我们将进一步调查最近的证据表明四肢可以磷酸化Ser和Tyr
通过X射线晶体学和分子动力学模拟的X射线晶体学的残基。这样
LIMK将成为通过各种“双重特异性”理解底物识别的一般模型
激酶家庭。最后,我们将研究与肌营养不良症相关的CDC42结合蛋白激酶
(MRCKS),一组主要的肢体激活GTPase Cdc42下游激活激酶,几乎没有什么是
目前已知。我们将使用结构,生物物理和生化方法来定义基本体系结构
MRCKβ研究并探测其激活如何通过底物适配器耦合与四肢的相互作用
蛋白质。总体而言,我们的研究将在我们对信号传导的分子水平理解中提供重大进步
Rho家族GTPases下游的途径会影响肌动蛋白细胞骨架的调节。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin.
- DOI:10.1158/2159-8290.cd-20-0797
- 发表时间:2021-06
- 期刊:
- 影响因子:28.2
- 作者:Torres-Ayuso P;An E;Nyswaner KM;Bensen RC;Ritt DA;Specht SI;Das S;Andresson T;Cachau RE;Liang RJ;Ries AL;Robinson CM;Difilippantonio S;Gouker B;Bassel L;Karim BO;Miller CJ;Turk BE;Morrison DK;Brognard J
- 通讯作者:Brognard J
PseudoGTPase domains in p190RhoGAP proteins: a mini-review.
p190RhoGAP 蛋白中的伪 GTP 酶结构域:小型综述。
- DOI:10.1042/bst20180481
- 发表时间:2018
- 期刊:
- 影响因子:3.9
- 作者:Stiegler,AmyL;Boggon,TitusJ
- 通讯作者:Boggon,TitusJ
Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology.
- DOI:10.1007/s00018-013-1532-9
- 发表时间:2014-05
- 期刊:
- 影响因子:8
- 作者:Fisher, Oriana S.;Boggon, Titus J.
- 通讯作者:Boggon, Titus J.
Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail.
独特的功能限制驱动丝切蛋白 N 末端调控尾部的保护。
- DOI:10.1101/2023.06.30.547189
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Sexton,JoelA;Potchernikov,Tony;Bibeau,JeffreyP;Casanova-Sepúlveda,Gabriela;Cao,Wenxiang;Lou,HuaJane;Boggon,TitusJ;DeLaCruz,EnriqueM;Turk,BenjaminE
- 通讯作者:Turk,BenjaminE
Homing in: Mechanisms of Substrate Targeting by Protein Kinases.
- DOI:10.1016/j.tibs.2018.02.009
- 发表时间:2018-05
- 期刊:
- 影响因子:13.8
- 作者:Miller CJ;Turk BE
- 通讯作者:Turk BE
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Titus Jonathon Boggon其他文献
Titus Jonathon Boggon的其他文献
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{{ truncateString('Titus Jonathon Boggon', 18)}}的其他基金
LIM domain kinases: regulation and substrate recognition
LIM 结构域激酶:调节和底物识别
- 批准号:
10443356 - 财政年份:2022
- 资助金额:
$ 9.36万 - 项目类别:
P21-activated kinases in cell-cell and cell-matrix adhesion signaling
细胞间和细胞基质粘附信号转导中的 P21 激活激酶
- 批准号:
10641867 - 财政年份:2020
- 资助金额:
$ 9.36万 - 项目类别:
P21-activated kinases in cell-cell and cell-matrix adhesion signaling
细胞间和细胞基质粘附信号转导中的 P21 激活激酶
- 批准号:
10436342 - 财政年份:2020
- 资助金额:
$ 9.36万 - 项目类别:
P21-activated kinases in cell-cell and cell-matrix adhesion signaling
细胞间和细胞基质粘附信号转导中的 P21 激活激酶
- 批准号:
10025961 - 财政年份:2020
- 资助金额:
$ 9.36万 - 项目类别:
P21-activated kinases in cell-cell and cell-matrix adhesion signaling
细胞间和细胞基质粘附信号转导中的 P21 激活激酶
- 批准号:
10250504 - 财政年份:2020
- 资助金额:
$ 9.36万 - 项目类别:
Human genetics and molecular mechanisms of Vein of Galen aneurysmal malformation
Galen静脉动脉瘤畸形的人类遗传学和分子机制
- 批准号:
10033009 - 财政年份:2020
- 资助金额:
$ 9.36万 - 项目类别:
Human Genetics and Molecular Mechanisms of Vein of Galen Aneurysmal Malformation
Galen 动脉瘤畸形静脉的人类遗传学和分子机制
- 批准号:
10673038 - 财政年份:2020
- 资助金额:
$ 9.36万 - 项目类别:
Investigating cellular function and biochemical mechanism for STK24-CCM3 complex
研究 STK24-CCM3 复合物的细胞功能和生化机制
- 批准号:
9020243 - 财政年份:2014
- 资助金额:
$ 9.36万 - 项目类别:
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