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Article ; Online: Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition.

Datta, Anirban / Sandilands, Emma / Mostov, Keith E / Bryant, David M

2017 Volume 40, Page(s) 91–98

Abstract: The formation of lumens in epithelial tissues requires apical-basal polarization of cells, and the co-ordination of this individual polarity collectively around a contiguous lumen. Signals from the Extracellular Matrix (ECM) instruct epithelia as to the ... ...

Abstract	The formation of lumens in epithelial tissues requires apical-basal polarization of cells, and the co-ordination of this individual polarity collectively around a contiguous lumen. Signals from the Extracellular Matrix (ECM) instruct epithelia as to the orientation of where basal, and thus consequently apical, surfaces should be formed. We report that this pathway is normally absent in Calu-3 human lung adenocarcinoma cells in 3-Dimensional culture, but that paracrine signals from MRC5 lung fibroblasts can induce correct orientation of polarity and acinar morphogenesis. We identify HGF, acting through the c-Met receptor, as the key polarity-inducing morphogen, which acts to activate β1-integrin-dependent adhesion. HGF and ECM-derived integrin signals co-operate via a c-Src-dependent inhibition of the RhoA-ROCK1 signalling pathway via p190A RhoGAP. This occurred via controlling localization of these signalling pathways to the ECM-abutting surface of cells in 3-Dimensional culture. Thus, stromal derived signals can influence morphogenesis in epithelial cells by controlling activation and localization of cell polarity pathways.
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Adenocarcinoma of Lung ; Carcinoma, Acinar Cell/genetics ; Carcinoma, Acinar Cell/pathology ; Cell Line, Tumor ; Cell Polarity/genetics ; Extracellular Matrix/genetics ; Fibroblasts/metabolism ; Guanine Nucleotide Exchange Factors/genetics ; Hepatocyte Growth Factor/genetics ; Humans ; Integrin beta1/genetics ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Paracrine Communication/genetics ; Repressor Proteins/genetics ; Signal Transduction/drug effects ; rho-Associated Kinases/genetics ; rhoA GTP-Binding Protein/genetics
Chemical Substances	ARHGAP35 protein, human ; Guanine Nucleotide Exchange Factors ; HGF protein, human ; Integrin beta1 ; Repressor Proteins ; RHOA protein, human (124671-05-2) ; Hepatocyte Growth Factor (67256-21-7) ; ROCK1 protein, human (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2017-09-06
Publishing country	England
Document type	Journal Article
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2017.09.001
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Zs.A 2579: Show issues

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Article ; Online: Discovery of novel N-acylpyrazoles as potent and selective thrombin inhibitors.

Short, Kevin M / Estiarte, M Angels / Pham, Son M / Williams, David C / Igoudin, Lev / Dash, Subhadra / Sandoval, Nichole / Datta, Anirban / Pozzi, Nicola / Di Cera, Enrico / Kita, David B

European journal of medicinal chemistry

2022 Volume 246, Page(s) 114855

Abstract: Direct oral anticoagulants (DOACs), which includes thrombin and factor Xa inhibitors, have emerged as the preferred therapeutics for thrombotic disorders, penetrating a market previously dominated by warfarin and heparin. This article describes the ... ...

Abstract	Direct oral anticoagulants (DOACs), which includes thrombin and factor Xa inhibitors, have emerged as the preferred therapeutics for thrombotic disorders, penetrating a market previously dominated by warfarin and heparin. This article describes the discovery and profiling of a novel series of N-acylpyrazoles, which act as selective, covalent, reversible, non-competitive inhibitors of thrombin. We describe in vitro stability issues associated with this chemotype and, importantly, demonstrate that N-acylpyrazoles successfully act in vivo as anticoagulants in basic thrombotic animal models. Crucially, this anticoagulant nature is unaccompanied by the higher bleeding risk profile that has become an undesirable characteristic of the DTIs and factor Xa inhibitors. We propose that the N-acylpyrazole chemotype shows intriguing promise as next-generation oral anticoagulants.
Language	English
Publishing date	2022-10-27
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2022.114855
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Article: Molecular Regulation of Lumen Morphogenesis

Datta, Anirban / Bryant, David M / Mostov, Keith E

Current biology. 2011 Feb. 8, v. 21, no. 3

2011

Abstract: The asymmetric polarization of cells allows specialized functions to be performed at discrete subcellular locales. Spatiotemporal coordination of polarization between groups of cells allowed the evolution of metazoa. For instance, coordinated apical- ... ...

Abstract	The asymmetric polarization of cells allows specialized functions to be performed at discrete subcellular locales. Spatiotemporal coordination of polarization between groups of cells allowed the evolution of metazoa. For instance, coordinated apical-basal polarization of epithelial and endothelial cells allows transport of nutrients and metabolites across cell barriers and tissue microenvironments. The defining feature of such tissues is the presence of a central, interconnected luminal network. Although tubular networks are present in seemingly different organ systems, such as the kidney, lung, and blood vessels, common underlying principles govern their formation. Recent studies using in vivo and in vitro models of lumen formation have shed new light on the molecular networks regulating this fundamental process. We here discuss progress in understanding common design principles underpinning de novo lumen formation and expansion.
Keywords	blood vessels ; endothelial cells ; evolution ; kidneys ; metabolites ; models ; morphogenesis ; nutrients
Language	English
Dates of publication	2011-0208
Size	p. R126-R136.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2010.12.003
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Article ; Online: Molecular regulation of lumen morphogenesis.

Datta, Anirban / Bryant, David M / Mostov, Keith E

Current biology : CB

2011 Volume 21, Issue 3, Page(s) R126–36

Abstract	The asymmetric polarization of cells allows specialized functions to be performed at discrete subcellular locales. Spatiotemporal coordination of polarization between groups of cells allowed the evolution of metazoa. For instance, coordinated apical-basal polarization of epithelial and endothelial cells allows transport of nutrients and metabolites across cell barriers and tissue microenvironments. The defining feature of such tissues is the presence of a central, interconnected luminal network. Although tubular networks are present in seemingly different organ systems, such as the kidney, lung, and blood vessels, common underlying principles govern their formation. Recent studies using in vivo and in vitro models of lumen formation have shed new light on the molecular networks regulating this fundamental process. We here discuss progress in understanding common design principles underpinning de novo lumen formation and expansion.
MeSH term(s)	Animals ; Body Patterning ; Cell Communication ; Cell Differentiation ; Cell Polarity ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Epithelial Cells/physiology ; Epithelium/anatomy & histology ; Epithelium/embryology ; Epithelium/metabolism ; Extracellular Matrix/metabolism ; Extracellular Matrix/physiology ; Humans ; Models, Biological ; Proteins/physiology ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription Factors/physiology
Chemical Substances	Proteins ; Transcription Factors
Language	English
Publishing date	2011-02-12
Publishing country	England
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	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2010.12.003
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Zs.A 3208: Show issues

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Article ; Online: MDCK cystogenesis driven by cell stabilization within computational analogues.

Engelberg, Jesse A / Datta, Anirban / Mostov, Keith E / Hunt, C Anthony

PLoS computational biology

2011 Volume 7, Issue 4, Page(s) e1002030

Abstract: The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even ... ...

Abstract	The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even simple morphogenesis remain unclear. For example, are specific cell actions tightly coupled to the characteristics of the cell's environment or are they more often cell state dependent? How does the single lumen, single cell layer cyst consistently emerge from a variety of cell actions? To improve insight, we instantiated in silico analogues that used hypothesized cell behavior mechanisms to mimic MDCK cystogenesis. We tested them through in vitro experimentation and quantitative validation. We observed novel growth patterns, including a cell behavior shift that began around day five of growth. We created agent-oriented analogues that used the cellular Potts model along with an Iterative Refinement protocol. Following several refinements, we achieved a degree of validation for two separate mechanisms. Both survived falsification and achieved prespecified measures of similarity to cell culture properties. In silico components and mechanisms mapped to in vitro counterparts. In silico, the axis of cell division significantly affects lumen number without changing cell number or cyst size. Reducing the amount of in silico luminal cell death had limited effect on cystogenesis. Simulations provide an observable theory for cystogenesis based on hypothesized, cell-level operating principles.
MeSH term(s)	Animals ; Apoptosis ; Cell Adhesion ; Cell Culture Techniques/methods ; Cell Death ; Cell Line ; Cell Nucleus/metabolism ; Computational Biology/methods ; Computer Simulation ; Cysts/pathology ; Dogs ; Models, Biological ; Software ; Tight Junctions
Language	English
Publishing date	2011-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1002030
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Article ; Online: Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization.

Roland, Joseph T / Bryant, David M / Datta, Anirban / Itzen, Aymelt / Mostov, Keith E / Goldenring, James R

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

2011 Volume 108, Issue 7, Page(s) 2789–2794

Abstract: The Rab GTPases are the largest family of proteins regulating membrane traffic. Rab proteins form a nidus for the assembly of multiprotein complexes on distinct vesicle membranes to regulate particular membrane trafficking pathways. Recent investigations ...

Abstract	The Rab GTPases are the largest family of proteins regulating membrane traffic. Rab proteins form a nidus for the assembly of multiprotein complexes on distinct vesicle membranes to regulate particular membrane trafficking pathways. Recent investigations have demonstrated that Myosin Vb (Myo5B) is an effector for Rab8a, Rab10, and Rab11a, all of which are implicated in regulating different pathways for recycling of proteins to the plasma membrane. It remains unclear how specific interactions of Myo5B with individual Rab proteins can lead to specificity in the regulation of alternate trafficking pathways. We examined the relative contributions of Rab/Myo5B interactions with specific pathways using Myo5B mutants lacking binding to either Rab11a or Rab8a. Myo5B Q1300L and Y1307C mutations abolished Rab8a association, whereas Myo5B Y1714E and Q1748R mutations uncoupled association with Rab11a. Expression of Myo5B tails containing these mutants demonstrated that Rab11a, but not Rab8a, was required for recycling of transferrin in nonpolarized cells. In contrast, in polarized epithelial cyst cultures, Myo5B was required for apical membrane trafficking and de novo lumen formation, dependent on association with both Rab8a and Rab11a. These data demonstrate that different combinations of Rab GTPase association with Myo5B control distinct membrane trafficking pathways.
MeSH term(s)	Animals ; Cell Line ; Cell Polarity/physiology ; DNA Primers/genetics ; Dogs ; Epithelial Cells/physiology ; Fluorescence Resonance Energy Transfer ; Humans ; Immunohistochemistry ; Membranes/metabolism ; Membranes/physiology ; Mice ; Multiprotein Complexes/metabolism ; Mutagenesis ; Myosin Heavy Chains/metabolism ; Myosin Type V/metabolism ; Protein Transport/physiology ; RNA Interference ; Transferrin/metabolism ; Transport Vesicles/metabolism ; Two-Hybrid System Techniques ; rab GTP-Binding Proteins/metabolism
Chemical Substances	DNA Primers ; MYO5B protein, human ; Multiprotein Complexes ; Transferrin ; Myosin Type V (EC 3.6.1.-) ; Myosin Heavy Chains (EC 3.6.4.1) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2011-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1010754108
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Zs.A 1148: Show issues

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Article ; Online: VE-1902-A direct thrombin inhibitor with reversible covalent mechanism of action shows efficacy with reduced bleeding in rodent models of thrombosis.

Thrombosis research

2020 Volume 190, Page(s) 112–121

Abstract: Introduction: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated ... ...

Abstract	Introduction: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated combination antithrombotic therapy. Here, we report on VE-1902, a member of a novel class of precision oral anticoagulants (PROACs) that combines effective anticoagulation with reduced bleeding in preclinical testing. Methods and results: Acting through covalent, reversible active-site modification of thrombin similar to a previously described molecule [1], VE-1902 shows potency and selectivity for thrombin inhibition in human plasma comparable to clinically relevant direct thrombin inhibitors (DTI) such as argatroban and dabigatran (thrombin generation assay ETP EC Conclusions: By leaving platelet activation following vascular injury mostly unaffected, VE-1902, and the PROACs more generally, represent a new generation of precision anticoagulants with reduced bleeding risk.
MeSH term(s)	Animals ; Anticoagulants/pharmacology ; Anticoagulants/therapeutic use ; Antithrombins ; Hemorrhage/chemically induced ; Hemorrhage/drug therapy ; Humans ; Rodentia ; Thrombin ; Thrombosis/drug therapy
Chemical Substances	Anticoagulants ; Antithrombins ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2020-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	121852-9
ISSN	1879-2472 ; 0049-3848
ISSN (online)	1879-2472
ISSN	0049-3848
DOI	10.1016/j.thromres.2020.04.020
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Article ; Online: Pseudomonas aeruginosa interacts with epithelial cells rapidly forming aggregates that are internalized by a Lyn-dependent mechanism.

Lepanto, Paola / Bryant, David M / Rossello, Jéssica / Datta, Anirban / Mostov, Keith E / Kierbel, Arlinet

Cellular microbiology

2011 Volume 13, Issue 8, Page(s) 1212–1222

Abstract: Growing evidence is pointing to the importance of multicellular bacterial structures in the interaction of pathogenic bacteria with their host. Transition from planktonic to host cell-associated multicellular structures is an essential infection step ... ...

Abstract	Growing evidence is pointing to the importance of multicellular bacterial structures in the interaction of pathogenic bacteria with their host. Transition from planktonic to host cell-associated multicellular structures is an essential infection step that has not been described for the opportunistic human pathogen Pseudomonas aeruginosa. In this study we show that P. aeruginosa interacts with the surface of epithelial cells mainly forming aggregates. Dynamics of aggregate formation typically follow a sigmoidal curve. First, a single bacterium attaches at cell-cell junctions. This is followed by rapid recruitment of free-swimming bacteria and association of bacterial cells resulting in the formation of an aggregate on the order of minutes. Aggregates are associated with phosphatidylinositol 3,4,5-trisphosphate (PIP3)-enriched host cell membrane protrusions. We further show that aggregates can be rapidly internalized into epithelial cells. Lyn, a member of the Src family tyrosine kinases previously implicated in P. aeruginosa infection, mediates both PIP3-enriched protrusion formation and aggregate internalization. Our results establish the first framework of principles that define P. aeruginosa transition to multicellular structures during interaction with host cells.
MeSH term(s)	Animals ; Cell Line ; Dogs ; Endocytosis ; Epithelial Cells/microbiology ; Host-Pathogen Interactions ; Microscopy, Electron ; Microscopy, Fluorescence ; Pseudomonas aeruginosa/pathogenicity ; Time Factors ; src-Family Kinases/metabolism
Chemical Substances	lyn protein-tyrosine kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2011-05-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1468320-9
ISSN	1462-5822 ; 1462-5814
ISSN (online)	1462-5822
ISSN	1462-5814
DOI	10.1111/j.1462-5822.2011.01611.x
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Article: Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization

Roland, Joseph T / Bryant, David M / Datta, Anirban / Itzen, Aymelt / Mostov, Keith E / Goldenring, James R

Proceedings of the National Academy of Sciences of the United States of America. 2011 Feb. 15, v. 108, no. 7

2011

Abstract	The Rab GTPases are the largest family of proteins regulating membrane traffic. Rab proteins form a nidus for the assembly of multiprotein complexes on distinct vesicle membranes to regulate particular membrane trafficking pathways. Recent investigations have demonstrated that Myosin Vb (Myo5B) is an effector for Rab8a, Rab10, and Rab11a, all of which are implicated in regulating different pathways for recycling of proteins to the plasma membrane. It remains unclear how specific interactions of Myo5B with individual Rab proteins can lead to specificity in the regulation of alternate trafficking pathways. We examined the relative contributions of Rab/Myo5B interactions with specific pathways using Myo5B mutants lacking binding to either Rab11a or Rab8a. Myo5B Q1300L and Y1307C mutations abolished Rab8a association, whereas Myo5B Y1714E and Q1748R mutations uncoupled association with Rab11a. Expression of Myo5B tails containing these mutants demonstrated that Rab11a, but not Rab8a, was required for recycling of transferrin in nonpolarized cells. In contrast, in polarized epithelial cyst cultures, Myo5B was required for apical membrane trafficking and de novo lumen formation, dependent on association with both Rab8a and Rab11a. These data demonstrate that different combinations of Rab GTPase association with Myo5B control distinct membrane trafficking pathways.
Keywords	epithelium ; guanosinetriphosphatase ; multiprotein complexes ; mutants ; mutation ; myosin ; physiological transport ; plasma membrane ; transferrin
Language	English
Dates of publication	2011-0215
Size	p. 2789-2794.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1010754108
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Article ; Online: Reversible covalent direct thrombin inhibitors.

Sivaraja, Mohanram / Pozzi, Nicola / Rienzo, Matthew / Lin, Kenneth / Shiau, Timothy P / Clemens, Daniel M / Igoudin, Lev / Zalicki, Piotr / Chang, Stephanie S / Estiarte, M Angels / Short, Kevin M / Williams, David C / Datta, Anirban / Di Cera, Enrico / Kita, David B

PloS one

2018 Volume 13, Issue 8, Page(s) e0201377

Abstract: Introduction: In recent years, the traditional treatments for thrombotic diseases, heparin and warfarin, are increasingly being replaced by novel oral anticoagulants offering convenient dosing regimens, more predictable anticoagulant responses, and less ...

Abstract	Introduction: In recent years, the traditional treatments for thrombotic diseases, heparin and warfarin, are increasingly being replaced by novel oral anticoagulants offering convenient dosing regimens, more predictable anticoagulant responses, and less frequent monitoring. However, these drugs can be contraindicated for some patients and, in particular, their bleeding liability remains high. Methods: We have developed a new class of direct thrombin inhibitors (VE-DTIs) and have utilized kinetics, biochemical, and X-ray structural studies to characterize the mechanism of action and in vitro pharmacology of an exemplary compound from this class, Compound 1. Results: We demonstrate that Compound 1, an exemplary VE-DTI, acts through reversible covalent inhibition. Compound 1 inhibits thrombin by transiently acylating the active site S195 with high potency and significant selectivity over other trypsin-like serine proteases. The compound inhibits the binding of a peptide substrate with both clot-bound and free thrombin with nanomolar potency. Compound 1 is a low micromolar inhibitor of thrombin activity against endogenous substrates such as fibrinogen and a nanomolar inhibitor of the activation of protein C and thrombin-activatable fibrinolysis inhibitor. In the thrombin generation assay, Compound 1 inhibits thrombin generation with low micromolar potency but does not increase the lag time for thrombin formation. In addition, Compound 1 showed weak inhibition of clotting in PT and aPTT assays consistent with its distinctive profile in the thrombin generation assay. Conclusion: Compound 1, while maintaining strong potency comparable to the current DTIs, has a distinct mechanism of action which produces a differentiating pharmacological profile. Acting through reversible covalent inhibition, these direct thrombin inhibitors could lead to new anticoagulants with better combined efficacy and bleeding profiles.
MeSH term(s)	Antithrombins/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Models, Chemical ; Thrombin/chemistry
Chemical Substances	Antithrombins ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2018-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0201377
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