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  1. Article ; Online: Coupling during collective cell migration is controlled by a vinculin mechanochemical switch.

    Shoyer, T Curtis / Gates, Evan M / Cabe, Jolene I / Urs, Aarti N / Conway, Daniel E / Hoffman, Brenton D

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 50, Page(s) e2316456120

    Abstract: The ability of cells to move in a mechanically coupled, coordinated manner, referred to as collective cell migration, is central to many developmental, physiological, and pathophysiological processes. Limited understanding of how mechanical forces and ... ...

    Abstract The ability of cells to move in a mechanically coupled, coordinated manner, referred to as collective cell migration, is central to many developmental, physiological, and pathophysiological processes. Limited understanding of how mechanical forces and biochemical regulation interact to affect coupling has been a major obstacle to unravelling the underlying mechanisms. Focusing on the linker protein vinculin, we use a suite of Förster resonance energy transfer-based biosensors to probe its mechanical functions and biochemical regulation, revealing a switch that toggles vinculin between loadable and unloadable states. Perturbation of the switch causes covarying changes in cell speed and coordination, suggesting alteration of the friction within the system. Molecular scale modelling reveals that increasing levels of loadable vinculin increases friction, due to engagement of self-stabilizing catch bonds. Together, this work reveals a regulatory switch for controlling cell coupling and describes a paradigm for relating biochemical regulation, altered mechanical properties, and changes in cell behaviors.
    MeSH term(s) Vinculin/metabolism ; Cell Movement/physiology ; Mechanical Phenomena ; Fluorescence Resonance Energy Transfer ; Cell Adhesion/physiology
    Chemical Substances Vinculin (125361-02-6)
    Language English
    Publishing date 2023-12-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2316456120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Structure-Functional-Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands.

    Park, Hyejin / Urs, Aarti N / Zimmerman, Joseph / Liu, Chuan / Wang, Qiu / Urs, Nikhil M

    ACS medicinal chemistry letters

    2020  Volume 11, Issue 3, Page(s) 385–392

    Abstract: Loss of dopamine neurons is central to the manifestation of Parkinson's disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson's disease, can restore normal movement yet cause side-effects such as ... ...

    Abstract Loss of dopamine neurons is central to the manifestation of Parkinson's disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson's disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their functional selectivity. Here, we report structure-functional-selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.
    Language English
    Publishing date 2020-01-06
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.9b00575
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  3. Article: Construction, imaging, and analysis of FRET-based tension sensors in living cells.

    LaCroix, Andrew S / Rothenberg, Katheryn E / Berginski, Matthew E / Urs, Aarti N / Hoffman, Brenton D

    Methods in cell biology

    2015  Volume 125, Page(s) 161–186

    Abstract: Due to an increased appreciation for the importance of mechanical stimuli in many biological contexts, an interest in measuring the forces experienced by specific proteins in living cells has recently emerged. The development and use of Förster resonance ...

    Abstract Due to an increased appreciation for the importance of mechanical stimuli in many biological contexts, an interest in measuring the forces experienced by specific proteins in living cells has recently emerged. The development and use of Förster resonance energy transfer (FRET)-based molecular tension sensors has enabled these types of studies and led to important insights into the mechanisms those cells utilize to probe and respond to the mechanical nature of their surrounding environment. The process for creating and utilizing FRET-based tension sensors can be divided into three main parts: construction, imaging, and analysis. First we review several methods for the construction of genetically encoded FRET-based tension sensors, including restriction enzyme-based methods as well as the more recently developed overlap extension or Gibson Assembly protocols. Next, we discuss the intricacies associated with imaging tension sensors, including optimizing imaging parameters as well as common techniques for estimating artifacts within standard imaging systems. Then, we detail the analysis of such data and describe how to extract useful information from a FRET experiment. Finally, we provide a discussion on identifying and correcting common artifacts in the imaging of FRET-based tension sensors.
    MeSH term(s) Animals ; Artifacts ; Biomechanical Phenomena ; Biosensing Techniques ; Cell Survival ; Fibronectins/metabolism ; Fluorescence Resonance Energy Transfer/methods ; Humans ; Imaging, Three-Dimensional/methods ; Mice ; Vinculin/metabolism
    Chemical Substances Fibronectins ; Vinculin (125361-02-6)
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Journal Article
    ISSN 0091-679X
    ISSN 0091-679X
    DOI 10.1016/bs.mcb.2014.10.033
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Sphingosine regulates the transcription of CYP17 by binding to steroidogenic factor-1.

    Urs, Aarti N / Dammer, Eric / Sewer, Marion B

    Endocrinology

    2006  Volume 147, Issue 11, Page(s) 5249–5258

    Abstract: Steroidogenic factor (SF1, Ad4BP, NR5A1) is a nuclear receptor that is essential for steroid hormone biosynthesis and endocrine development. Recent crystallographic studies have found that phospholipids are ligands for SF1. In the present study, our aim ... ...

    Abstract Steroidogenic factor (SF1, Ad4BP, NR5A1) is a nuclear receptor that is essential for steroid hormone biosynthesis and endocrine development. Recent crystallographic studies have found that phospholipids are ligands for SF1. In the present study, our aim was to identify endogenous ligands for SF1 and characterize their functional significance in mediating cAMP-dependent transcription of human CYP17. Using tandem mass spectrometry, we show that in H295R adrenocortical cells, SF1 is bound to sphingosine (SPH) and lyso-sphingomyelin (lysoSM) under basal conditions and that cAMP stimulation decreases the amount of SPH and lysoSM bound to the receptor. Silencing both acid and neutral ceramidases using small interfering RNA induces CYP17 mRNA expression, suggesting that SPH acts as an inhibitory ligand. SPH antagonized the ability of cAMP and the coactivator steroid receptor coactivator-1 to increase CYP17 reporter gene activity. These studies demonstrate that SPH is a bonafide endogenous ligand for SF1 and a negative regulator of CYP17 gene expression.
    MeSH term(s) Binding Sites ; Binding, Competitive ; Cells, Cultured ; Cyclic AMP/physiology ; Gene Expression Regulation ; Homeodomain Proteins/chemistry ; Homeodomain Proteins/metabolism ; Humans ; Phosphorylcholine/analogs & derivatives ; Phosphorylcholine/metabolism ; RNA, Messenger/analysis ; Receptors, Cytoplasmic and Nuclear/chemistry ; Receptors, Cytoplasmic and Nuclear/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism ; Steroid 17-alpha-Hydroxylase/genetics ; Steroidogenic Factor 1 ; Transcription Factors/chemistry ; Transcription Factors/metabolism ; Transcription, Genetic
    Chemical Substances Homeodomain Proteins ; NR5A1 protein, human ; RNA, Messenger ; Receptors, Cytoplasmic and Nuclear ; Steroidogenic Factor 1 ; Transcription Factors ; sphingosine phosphorylcholine (10216-23-6) ; Phosphorylcholine (107-73-3) ; Cyclic AMP (E0399OZS9N) ; Steroid 17-alpha-Hydroxylase (EC 1.14.14.19) ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2006-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/en.2006-0355
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  5. Article ; Online: Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D

    Martini, Michael L / Liu, Jing / Ray, Caroline / Yu, Xufen / Huang, Xi-Ping / Urs, Aarti / Urs, Nikhil / McCorvy, John D / Caron, Marc G / Roth, Bryan L / Jin, Jian

    Journal of medicinal chemistry

    2019  Volume 62, Issue 7, Page(s) 3753–3772

    Abstract: G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream ... ...

    Abstract G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed functionally selective or biased ligands. A class of novel non-catechol G protein-biased agonists of the dopamine D
    MeSH term(s) Animals ; CHO Cells ; Catechols/pharmacology ; Cricetulus ; Dopamine Agonists/pharmacokinetics ; Dopamine Agonists/pharmacology ; HEK293 Cells ; Humans ; Receptors, Dopamine D1/antagonists & inhibitors ; Structure-Activity Relationship
    Chemical Substances Catechols ; DRD1 protein, human ; Dopamine Agonists ; Receptors, Dopamine D1 ; catechol (LF3AJ089DQ)
    Language English
    Publishing date 2019-03-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.9b00351
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Show issues Location:
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  6. Article: Steroidogenic factor-1 is a sphingolipid binding protein.

    Urs, Aarti N / Dammer, Eric / Kelly, Samuel / Wang, Elaine / Merrill, Alfred H / Sewer, Marion B

    Molecular and cellular endocrinology

    2007  Volume 265-266, Page(s) 174–178

    Abstract: Steroidogenic factor (SF1, NR5A1, Ad4BP) is an orphan nuclear receptor that is essential for steroid hormone-biosynthesis and endocrine development. Studies have found that the ability of this receptor to increase target gene expression can be regulated ... ...

    Abstract Steroidogenic factor (SF1, NR5A1, Ad4BP) is an orphan nuclear receptor that is essential for steroid hormone-biosynthesis and endocrine development. Studies have found that the ability of this receptor to increase target gene expression can be regulated by post-translational modification, subnuclear localization, and protein-protein interactions. Recent crystallographic studies and our mass spectrometric analyses of the endogenous receptor have demonstrated an integral role for ligand-binding in the control of SF1 transactivation activity. Herein, we discuss our findings that sphingosine is an endogenous ligand for SF1. These studies and the structural findings of others have demonstrated that the receptor can bind both sphingolipids and phospholipids. Thus, it is likely that multiple bioactive lipids are ligands for SF1 and that these lipids will differentially act to control SF1 activity in a context-dependent manner. Finally, these findings highlight a central role for bioactive lipids as mediators of trophic hormone-stimulated steroid hormone biosynthesis.
    MeSH term(s) Animals ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Sphingolipids/metabolism ; Sphingosine/metabolism ; Steroidogenic Factor 1 ; Steroids/biosynthesis ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcriptional Activation
    Chemical Substances Homeodomain Proteins ; NR5A1 protein, human ; Receptors, Cytoplasmic and Nuclear ; Sphingolipids ; Steroidogenic Factor 1 ; Steroids ; Transcription Factors ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2007-02
    Publishing country Ireland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 187438-x
    ISSN 1872-8057 ; 0303-7207
    ISSN (online) 1872-8057
    ISSN 0303-7207
    DOI 10.1016/j.mce.2006.12.016
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    Zs.A 1127: Show issues Location:
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  7. Article: Cyclic AMP-stimulated interaction between steroidogenic factor 1 and diacylglycerol kinase theta facilitates induction of CYP17.

    Li, Donghui / Urs, Aarti N / Allegood, Jeremy / Leon, Adam / Merrill, Alfred H / Sewer, Marion B

    Molecular and cellular biology

    2007  Volume 27, Issue 19, Page(s) 6669–6685

    Abstract: In the human adrenal cortex, adrenocorticotropin (ACTH) activates CYP17 transcription by promoting the binding of the nuclear receptor steroidogenic factor 1 (SF1) (Ad4BP, NR5A1) to the promoter. We recently found that sphingosine is an antagonist for ... ...

    Abstract In the human adrenal cortex, adrenocorticotropin (ACTH) activates CYP17 transcription by promoting the binding of the nuclear receptor steroidogenic factor 1 (SF1) (Ad4BP, NR5A1) to the promoter. We recently found that sphingosine is an antagonist for SF1 and inhibits cyclic AMP (cAMP)-dependent CYP17 gene transcription. The aim of the current study was to identify phospholipids that bind to SF1 and to characterize the mechanism by which ACTH/cAMP regulates the biosynthesis of this molecule(s). Using tandem mass spectrometry, we show that in H295R human adrenocortical cells, SF1 is bound to phosphatidic acid (PA). Activation of the ACTH/cAMP signal transduction cascade rapidly increases nuclear diacylglycerol kinase (DGK) activity and PA production. PA stimulates SF1-dependent transcription of CYP17 reporter plasmids, promotes coactivator recruitment, and induces the mRNA expression of CYP17 and several other steroidogenic genes. Inhibition of DGK activity attenuates the binding of SF1 to the CYP17 promoter, and silencing of DGK-theta expression inhibits cAMP-dependent CYP17 transcription. LXXLL motifs in DGK-theta mediate a direct interaction of SF1 with the kinase and may facilitate binding of PA to the receptor. We conclude that ACTH/cAMP stimulates PA production in the nucleus of H295R cells and that this increase in PA concentrations facilitates CYP17 induction.
    MeSH term(s) Adrenal Cortex/cytology ; Adrenal Cortex/physiology ; Adrenocorticotropic Hormone/metabolism ; Animals ; Cell Line ; Cell Nucleus/metabolism ; Cyclic AMP/metabolism ; Diacylglycerol Kinase/genetics ; Diacylglycerol Kinase/metabolism ; Enzyme Induction ; Gene Expression Regulation ; Genes, Reporter ; Humans ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Phosphatidic Acids/metabolism ; Phospholipids/metabolism ; Promoter Regions, Genetic ; RNA Polymerase II/metabolism ; Signal Transduction/physiology ; Steroid 17-alpha-Hydroxylase/genetics ; Steroid 17-alpha-Hydroxylase/metabolism ; Steroidogenic Factor 1/genetics ; Steroidogenic Factor 1/metabolism ; Two-Hybrid System Techniques
    Chemical Substances Isoenzymes ; NR5A1 protein, human ; Phosphatidic Acids ; Phospholipids ; Steroidogenic Factor 1 ; Adrenocorticotropic Hormone (9002-60-2) ; Cyclic AMP (E0399OZS9N) ; Steroid 17-alpha-Hydroxylase (EC 1.14.14.19) ; Diacylglycerol Kinase (EC 2.7.1.107) ; RNA Polymerase II (EC 2.7.7.-)
    Language English
    Publishing date 2007-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00355-07
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    Zs.A 1666: Show issues Location:
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