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Article ; Online: Application of the Gyrolab microfluidic platform to measure picomolar affinity of a PD-L1-binding Adnectin™ radioligand for positron emission tomography.

Dai, Zhou / Juneja, Juhi / Schneeweis, Lumelle / Cohen, Daniel / Marsilio, Frank / Morin, Paul / DasGupta, Ruchira

2020 Volume 69, Issue 3, Page(s) 200–205

Abstract: ... Advances ... ...

Abstract	Advances in
MeSH term(s)	B7-H1 Antigen/chemistry ; B7-H1 Antigen/genetics ; B7-H1 Antigen/isolation & purification ; Humans ; Ligands ; Microfluidics/methods ; Positron-Emission Tomography/methods ; Protein Binding/genetics
Chemical Substances	B7-H1 Antigen ; Ligands
Language	English
Publishing date	2020-07-16
Publishing country	England
Document type	Journal Article
ZDB-ID	48453-2
ISSN	1940-9818 ; 0736-6205
ISSN (online)	1940-9818
ISSN	0736-6205
DOI	10.2144/btn-2020-0080
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Article ; Online: Application of the Gyrolab microfluidic platform to measure picomolar affinity of a PD-L1-binding Adnectin™ radioligand for positron emission tomography

Zhou Dai / Juhi Juneja / Lumelle Schneeweis / Daniel Cohen / Frank Marsilio / Paul Morin / Ruchira DasGupta

BioTechniques, Vol 69, Iss 3, Pp 200-

2020 Volume 205

Abstract: Advances in in vitro display and protein engineering yield therapeutics with affinities in the picomolar range. The Gyrolab® microfluidics platform uses the kinetic exclusion assay principle to measure subnanomolar solution affinities. This work ... ...

Abstract	Advances in in vitro display and protein engineering yield therapeutics with affinities in the picomolar range. The Gyrolab® microfluidics platform uses the kinetic exclusion assay principle to measure subnanomolar solution affinities. This work describes application of the Gyrolab solution affinity module and the new multi-curve analysis feature to determine affinity of the PD-L1 Adnectin™ positron emission tomography radioligand, which was measured as 20 pM for human PD-L1. We also report key parameters that affect assay signal-to-background ratio and data quality, such as detection reagent concentration. Gyrolab offers the necessary throughput for rapid assay development with low sample consumption, as demonstrated in this study, which also provides helpful tips for assay optimization for solution affinity measurement.
Keywords	equilibrium dissociation constant (KD) ; kinetic exclusion assay ; multi-curve analysis ; PD-L1-binding Adnectin ; signal/background ratio ; solution affinity ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Future Science Ltd
Document type	Article ; Online
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Article ; Online: Role of G12 proteins in oncogenesis and metastasis.

Juneja, Juhi / Casey, Patrick J

British journal of pharmacology

2009 Volume 158, Issue 1, Page(s) 32–40

Abstract: The G12 subfamily of heterotrimeric guanine nucleotide-binding proteins consists of two alpha subunits, G alpha12 and G alpha13. These proteins mediate signalling via G protein-coupled receptors and have been implicated in various physiological and ... ...

Abstract	The G12 subfamily of heterotrimeric guanine nucleotide-binding proteins consists of two alpha subunits, G alpha12 and G alpha13. These proteins mediate signalling via G protein-coupled receptors and have been implicated in various physiological and pathophysiological processes. A number of direct and indirect effectors of G alpha12 and G alpha13 have been identified that mediate, or have been proposed to mediate, the diverse cellular responses accompanying activation of G12 proteins. This review describes the signalling pathways and cellular events stimulated by G12 proteins, with a particular emphasis on processes that are important in regulating cell migration and invasion, and could potentially be involved in the pathophysiology of cancer metastasis. Experimental findings directly implicating G12 proteins in the spread of metastatic disease are also summarized, indicating the importance of targeted inhibition of G12 signalling as a potential therapeutic option for locally advanced and metastatic disease.
MeSH term(s)	Animals ; Cell Movement/physiology ; Drug Delivery Systems ; GTP-Binding Protein alpha Subunits, G12-G13/metabolism ; GTP-Binding Protein alpha Subunits, G12-G13/physiology ; Humans ; Neoplasm Invasiveness/pathology ; Neoplasm Invasiveness/physiopathology ; Neoplasm Invasiveness/prevention & control ; Neoplasms/chemistry ; Neoplasms/etiology ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/physiopathology ; Signal Transduction/drug effects ; Signal Transduction/physiology
Chemical Substances	GTP-Binding Protein alpha Subunits, G12-G13 (EC 3.6.5.1)
Language	English
Publishing date	2009-04-30
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/j.1476-5381.2009.00180.x
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Article ; Online: G12 signaling through c-Jun NH2-terminal kinase promotes breast cancer cell invasion.

Juneja, Juhi / Cushman, Ian / Casey, Patrick J

PloS one

2011 Volume 6, Issue 11, Page(s) e26085

Abstract: Signaling through the heterotrimeric G protein, G12, via Rho induces a striking increase in breast cancer cell invasion. In this study, evidence is provided that the c-Jun NH(2)-terminal kinase (JNK) is a key downstream effector of G12 on this pathway. ... ...

Abstract	Signaling through the heterotrimeric G protein, G12, via Rho induces a striking increase in breast cancer cell invasion. In this study, evidence is provided that the c-Jun NH(2)-terminal kinase (JNK) is a key downstream effector of G12 on this pathway. Expression of constitutively-active Gα12 or activation of G12 signaling by thrombin leads to increased JNK and c-Jun phosphorylation. Pharmacologic inhibition of JNK or knockdown of JNK expression by siRNA significantly decreases G12-induced JNK activation as well as the ability of breast cancer cells to invade a reconstituted basement membrane. Furthermore, expression of dominant-negative Rho or treatment of cells with an inhibitor of the Rho kinase, ROCK, reduces G12-induced JNK and c-Jun activation, and ROCK inhibitor treatment also inhibits G12-induced cellular invasion. JNK knockdown or ROCK inhibitor treatment has no effect on activation of Rho by G12. Taken together, our data indicate that JNK activation is required for G12-induced invasion of breast cancer cells and that JNK is downstream of Rho and ROCK on this pathway. This study implicates a G12-stimulated mitogen-activated protein kinase cascade in cancer cell invasion, and supports a role for JNK in cancer progression.
MeSH term(s)	Basement Membrane ; Breast Neoplasms/pathology ; Female ; GTP-Binding Protein alpha Subunits, G12-G13/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Neoplasm Invasiveness ; Phosphorylation ; Signal Transduction ; rho-Associated Kinases/metabolism ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	rho-Associated Kinases (EC 2.7.11.1) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; GTP-Binding Protein alpha Subunits, G12-G13 (EC 3.6.5.1) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2011-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0026085
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Article ; Online: G12 signaling through c-Jun NH2-terminal kinase promotes breast cancer cell invasion.

Juhi Juneja / Ian Cushman / Patrick J Casey

PLoS ONE, Vol 6, Iss 11, p e

2011 Volume 26085

Abstract	Signaling through the heterotrimeric G protein, G12, via Rho induces a striking increase in breast cancer cell invasion. In this study, evidence is provided that the c-Jun NH(2)-terminal kinase (JNK) is a key downstream effector of G12 on this pathway. Expression of constitutively-active Gα12 or activation of G12 signaling by thrombin leads to increased JNK and c-Jun phosphorylation. Pharmacologic inhibition of JNK or knockdown of JNK expression by siRNA significantly decreases G12-induced JNK activation as well as the ability of breast cancer cells to invade a reconstituted basement membrane. Furthermore, expression of dominant-negative Rho or treatment of cells with an inhibitor of the Rho kinase, ROCK, reduces G12-induced JNK and c-Jun activation, and ROCK inhibitor treatment also inhibits G12-induced cellular invasion. JNK knockdown or ROCK inhibitor treatment has no effect on activation of Rho by G12. Taken together, our data indicate that JNK activation is required for G12-induced invasion of breast cancer cells and that JNK is downstream of Rho and ROCK on this pathway. This study implicates a G12-stimulated mitogen-activated protein kinase cascade in cancer cell invasion, and supports a role for JNK in cancer progression.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance.

Tan, Catherine L / Kuchroo, Juhi R / Sage, Peter T / Liang, Dan / Francisco, Loise M / Buck, Jessica / Thaker, Youg Raj / Zhang, Qianxia / McArdel, Shannon L / Juneja, Vikram R / Lee, Sun Jung / Lovitch, Scott B / Lian, Christine / Murphy, George F / Blazar, Bruce R / Vignali, Dario A A / Freeman, Gordon J / Sharpe, Arlene H

The Journal of experimental medicine

2020 Volume 218, Issue 1

Abstract: Inhibitory signals through the PD-1 pathway regulate T cell activation, T cell tolerance, and T cell exhaustion. Studies of PD-1 function have focused primarily on effector T cells. Far less is known about PD-1 function in regulatory T (T reg) cells. To ... ...

Abstract	Inhibitory signals through the PD-1 pathway regulate T cell activation, T cell tolerance, and T cell exhaustion. Studies of PD-1 function have focused primarily on effector T cells. Far less is known about PD-1 function in regulatory T (T reg) cells. To study the role of PD-1 in T reg cells, we generated mice that selectively lack PD-1 in T reg cells. PD-1-deficient T reg cells exhibit an activated phenotype and enhanced immunosuppressive function. The in vivo significance of the potent suppressive capacity of PD-1-deficient T reg cells is illustrated by ameliorated experimental autoimmune encephalomyelitis (EAE) and protection from diabetes in nonobese diabetic (NOD) mice lacking PD-1 selectively in T reg cells. We identified reduced signaling through the PI3K-AKT pathway as a mechanism underlying the enhanced suppressive capacity of PD-1-deficient T reg cells. Our findings demonstrate that cell-intrinsic PD-1 restraint of T reg cells is a significant mechanism by which PD-1 inhibitory signals regulate T cell tolerance and autoimmunity.
MeSH term(s)	Animals ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/genetics ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Immune Tolerance ; Mice ; Mice, Inbred NOD ; Mice, Neurologic Mutants ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/immunology ; Programmed Cell Death 1 Receptor/genetics ; Programmed Cell Death 1 Receptor/immunology ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2020-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20182232
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Ua VI Zs.107: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article: Characterization of the unfolding of ribonuclease a by a pulsed hydrogen exchange study: evidence for competing pathways for unfolding.

Juneja, Juhi / Udgaonkar, Jayant B

Biochemistry

2002 Volume 41, Issue 8, Page(s) 2641–2654

Abstract: The unfolding of ribonuclease A was studied in 5.2 M guanidine hydrochloride at pH 8 and 10 degrees C using multiple optical probes, native-state hydrogen exchange (HX), and pulse labeling by hydrogen exchange. First, native-state HX studies were used to ...

Abstract	The unfolding of ribonuclease A was studied in 5.2 M guanidine hydrochloride at pH 8 and 10 degrees C using multiple optical probes, native-state hydrogen exchange (HX), and pulse labeling by hydrogen exchange. First, native-state HX studies were used to demonstrate that the protein exists in two slowly interconverting forms under equilibrium native conditions: a predominant exchange-incompetent N form and an alternative ensemble of conformations, N(I), in which some amide hydrogens are fully exposed to exchange. Pulsed HX studies indicated that, during unfolding, the rates of exposure to exchange with solvent protons were similar for all backbone NH probe protons. It is shown that two parallel routes of unfolding are available to the predominant N conformation as soon as it encounters strong unfolding conditions. A fraction of molecules appears to rapidly form N(I) on one route. On the other route an exchange-incompetent intermediate state ensemble, I(U)(2), is formed. The kinetics of unfolding measured by far-UV circular dichroism (CD) were faster than those measured by near-UV CD and intrinsic tyrosine fluorescence of the protein. The logarithms of the rate constants of the unfolding reaction measured by all three optical probes also showed a nonlinear dependence on GdnHCl concentration. All of the data suggest that N(I) and I(U)(2) are nativelike in their secondary and tertiary structures. While N(I) unfolds directly to the fully exchange-competent unfolded state (U), I(U)(2) forms another intermediate I(U)(3) which then unfolds to U. I(U)(3) is devoid of all native alpha-helical secondary structure and has only 30% of the tertiary interactions still intact. Since the rates of global unfolding measured by near-UV CD and fluorescence agree well with the rates of exposure determined for all of the backbone NH probe protons, it appears that the rate-limiting step for the unfolding of RNase A is the dissolution of the entire native tertiary structure and penetration of water into the hydrophobic core.
MeSH term(s)	Animals ; Cattle ; Circular Dichroism ; Hydrogen/chemistry ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Pancreas/enzymology ; Protein Conformation ; Protein Denaturation ; Ribonuclease, Pancreatic/chemistry ; Ribonuclease, Pancreatic/metabolism ; Spectrophotometry, Ultraviolet
Chemical Substances	Hydrogen (7YNJ3PO35Z) ; Ribonuclease, Pancreatic (EC 3.1.27.5)
Language	English
Publishing date	2002-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi011480p
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Article: Native and nonnative conformational preferences in the urea-unfolded state of barstar.

Bhavesh, Neel S / Juneja, Juhi / Udgaonkar, Jayant B / Hosur, Ramakrishna V

Protein science : a publication of the Protein Society

2004 Volume 13, Issue 12, Page(s) 3085–3091

Abstract: The refolding of barstar from its urea-unfolded state has been studied extensively using various spectroscopic probes and real-time NMR, which provide global and residue-specific information, respectively, about the folding process. Here, a preliminary ... ...

Abstract	The refolding of barstar from its urea-unfolded state has been studied extensively using various spectroscopic probes and real-time NMR, which provide global and residue-specific information, respectively, about the folding process. Here, a preliminary structural characterization by NMR of barstar in 8 M urea has been carried out at pH 6.5 and 25 degrees C. Complete backbone resonance assignments of the urea-unfolded protein were obtained using the recently developed three-dimensional NMR techniques of HNN and HN(C)N. The conformational propensities of the polypeptide backbone in the presence of 8 M urea have been estimated by examining deviations of secondary chemical shifts from random coil values. For some residues that belong to helices in native barstar, 13C(alpha) and 13CO secondary shifts show positive deviations in the urea-unfolded state, indicating that these residues have propensities toward helical conformations. These residues are, however, juxtaposed by residues that display negative deviations indicative of propensities toward extended conformations. Thus, segments that are helical in native barstar are unlikely to preferentially populate the helical conformation in the unfolded state. Similarly, residues belonging to beta-strands 1 and 2 of native barstar do not appear to show any conformational preferences in the unfolded state. On the other hand, residues belonging to the beta-strand 3 segment show weak nonnative helical conformational preferences in the unfolded state, indicating that this segment may possess a weak preference for populating a helical conformation in the unfolded state.
MeSH term(s)	Bacterial Proteins/chemistry ; Hydrogen-Ion Concentration ; Magnetic Resonance Spectroscopy ; Protein Conformation ; Protein Denaturation ; Protein Folding ; Solvents/chemistry ; Urea/chemistry
Chemical Substances	Bacterial Proteins ; Solvents ; barstar protein, Bacillus amyloliquefaciens (37328-61-3) ; Urea (8W8T17847W)
Language	English
Publishing date	2004-11-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1110/ps.04805204
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: NMR identification and characterization of the flexible regions in the 160 kDa molten globule-like aggregate of barstar at low pH.

Juneja, Juhi / Bhavesh, Neel S / Udgaonkar, Jayant B / Hosur, Ramakrishna V

Biochemistry

2002 Volume 41, Issue 31, Page(s) 9885–9899

Abstract: Barstar is known to form a molten globule-like A form below pH 4. This form exists as a soluble aggregate of 16 monomeric subunits, and appears to remain homogeneous in solution for at least two weeks. Here, structural characterization by NMR of the ... ...

Abstract	Barstar is known to form a molten globule-like A form below pH 4. This form exists as a soluble aggregate of 16 monomeric subunits, and appears to remain homogeneous in solution for at least two weeks. Here, structural characterization by NMR of the flexible regions in the A form of barstar has been carried out at pH 2.7 and 25 degrees C. Significantly, the A form appears to be a symmetrical aggregate. Using the recently described fast assignment strategy from HNN and HN(C)N spectra, along with the standard triple resonance and three-dimensional NMR experiments, the flexible segment of the aggregate has been identified to belong largely to the N-terminal end of the polypeptide chain; sequential connectivities were obtained for the first 20 residues (except two) from these experiments. This segment is free in each of the monomeric subunits, and does not form a part of the aggregated core of the A form. The secondary chemical shifts of these residues suggest propensity toward an extended structure. Their (3)J(HN,H)(alpha) coupling constants have values corresponding to those in a random coil structure. However, a few medium-range NOEs, some of them involving side chain atoms, are observed between some residues in this segment. The lowered temperature coefficients of the H(N) chemical shifts compared to random coil values indicate possibilities of some hydrogen bonding in this region. Analysis of the (15)N relaxation parameters and reduced spectral density functions, in particular the negative values of heteronuclear NOEs, indicates large-amplitude high-frequency motions in the N-terminal segments; the first three residues show more negative NOEs than the others. The (15)N transverse relaxation rates and the J(0) spectral density values for residues Ser12 and Ser69 are significantly larger than for the rest, indicating some microsecond to millisecond time scale conformational exchange contributions to the relaxation of these residues. Taken all together, the data suggest that the A form of barstar is an aggregate with a rigid core, but with the N-terminal 20 residues of each of the monomeric subunits, in a highly dynamic random coil conformation which shows transient local ordering of structure. The N-terminal segment, anchored to the aggregated core, exhibits free-flight motion.
MeSH term(s)	Bacterial Proteins/chemistry ; Hydrogen-Ion Concentration ; Light ; Nuclear Magnetic Resonance, Biomolecular ; Recombinant Proteins/chemistry ; Scattering, Radiation
Chemical Substances	Bacterial Proteins ; Recombinant Proteins ; barstar protein, Bacillus amyloliquefaciens (37328-61-3)
Language	English
Publishing date	2002-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi026034w
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Article: Selective uncoupling of G alpha 12 from Rho-mediated signaling.

Meigs, Thomas E / Juneja, Juhi / DeMarco, C Todd / Stemmle, Laura N / Kaplan, Daniel D / Casey, Patrick J

The Journal of biological chemistry

2005 Volume 280, Issue 18, Page(s) 18049–18055

Abstract: The heterotrimeric G protein G(12) has been implicated in such cellular regulatory processes as cytoskeletal rearrangement, cell-cell adhesion, and oncogenic transformation. Although the activated alpha-subunit of G(12) has been shown to interact ... ...

Abstract	The heterotrimeric G protein G(12) has been implicated in such cellular regulatory processes as cytoskeletal rearrangement, cell-cell adhesion, and oncogenic transformation. Although the activated alpha-subunit of G(12) has been shown to interact directly with a number of protein effectors, the roles of many of these protein-protein interactions in G(12)-mediated cell physiology are poorly understood. To begin dissecting the specific cellular pathways engaged upon G(12) activation, we produced a series of substitution mutants in the regions of Galpha(12) predicted to play a role in effector binding. Here we report the identification and characterization of an altered form of Galpha(12) that is functionally uncoupled from signaling through the monomeric G protein Rho, a protein known to propagate several Galpha(12)-mediated signals. This mutant of Galpha(12) fails to bind the Rho-specific guanine nucleotide exchange factors p115RhoGEF and LARG (leukemia-associated RhoGEF), fails to stimulate Rho-dependent transcriptional activation, and fails to trigger activation of RhoA and the Rho-mediated cellular responses of cell rounding and c-jun N-terminal kinase activation. Importantly, this mutant of Galpha(12) retains coupling to the effector protein E-cadherin, as evidenced by its ability both to bind E-cadherin in vitro and to disrupt E-cadherin-mediated cell-cell adhesion. Furthermore, this mutant retains the ability to trigger beta-catenin release from the cytoplasmic domain of cadherin. This identification of a variant of Galpha(12) that is selectively uncoupled from one signaling pathway while retaining signaling capacity through a separate pathway will facilitate investigations into the mechanisms through which G(12) proteins mediate diverse biological responses.
MeSH term(s)	Cadherins/physiology ; Cell Line ; GTP-Binding Protein alpha Subunits, G12-G13/metabolism ; Guanine Nucleotide Exchange Factors/physiology ; Humans ; Protein Binding/physiology ; Rho Guanine Nucleotide Exchange Factors ; Signal Transduction/physiology
Chemical Substances	Cadherins ; Guanine Nucleotide Exchange Factors ; Rho Guanine Nucleotide Exchange Factors ; GTP-Binding Protein alpha Subunits, G12-G13 (EC 3.6.5.1)
Language	English
Publishing date	2005-03-03
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, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M500445200
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