Topological control of cytokine receptor signaling induces differential effects in hematopoiesis

Mohan, Kritika; Ueda, George; Kim, Ah Ram; Jude, Kevin M.; Fallas, Jorge A.; Guo, Yu; Hafer, Maximillian; Miao, Yi; Saxton, Robert A.; Piehler, Jacob; Sankaran, Vijay G.; Baker, David; Garcia, K. Christopher

doi:10.1126/science.aav7532

Title: Topological control of cytokine receptor signaling induces differential effects in hematopoiesis

Journal Article · Thu May 23 00:00:00 EDT 2019 · Science

DOI:https://doi.org/10.1126/science.aav7532· OSTI ID:1532487

^[1];

^[2];

^[3];

^[4];

^[2];

^[5];

^[6];

^[1];

^[7];

^[8];

^[3];

^[9];

^[10]

Stanford Univ., CA (United States). School of Medicine
Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry, and Inst. for Protein Design
Boston Children’s Hospital and Harvard Medical School, Boston, MA (United States). Division of Hematology/Oncology, The Manton Center for Orphan Disease Research; Harvard Medical School, Boston, MA (United States). Dana-Farber Cancer Inst., Dept. of Pediatric Oncology; Broad Inst. of MIT and Harvard, Cambridge, MA (United States)
Stanford Univ., CA (United States). Howard Hughes Medical Inst.
Nankai Univ., Tianjin (China). State Key Lab. of Medicinal Chemical Biology and College of Pharmacy
Univ. of Osnabrück, Osnabrück (Germany). Division of Biophysics, Dept. of Biology
Stanford Univ., CA (United States). School of Medicine, and Howard Hughes Medical Inst.
Univ. of Osnabrück, Osnabrück (Germany). Division of Biophysics, Dept. of Biology, and Center for Cellular Nanoanalytics
Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry, and Inst. for Protein Design, and Howard Hughes Medical Inst.
Stanford Univ., CA (United States). School of Medicine, Howard Hughes Medical Inst., and Dept. of Structural Biology

Although tunable signaling by G protein–coupled receptors can be exploited through medicinal chemistry, a comparable pharmacological approach has been lacking for the modulation of signaling through dimeric receptors, such as those for cytokines. We present a strategy to modulate cytokine receptor signaling output by use of a series of designed C2-symmetric cytokine mimetics, based on the designed ankyrin repeat protein (DARPin) scaffold, that can systematically control erythropoietin receptor (EpoR) dimerization orientation and distance between monomers. We sampled a range of EpoR geometries by varying intermonomer angle and distance, corroborated by several ligand-EpoR complex crystal structures. Across the range, we observed full, partial, and biased agonism as well as stage-selective effects on hematopoiesis. Lastly, this surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); German Research Foundation (DFG)

Grant/Contract Number:: AC02-76SF00515; AC02-06CH11357; AC02-05CH11231; S10OD021832; R01-AI51321; T32HL066987; R01 DK103794; R33 HL120791; 1S10OD012289-01A1

OSTI ID:: 1532487

Journal Information:: Science, Vol. 364, Issue 6442; ISSN 0036-8075

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 52 works

Citation information provided by
Web of Science

References (73)

Orientation-specific signalling by thrombopoietin receptor dimers: Orientation-specific TpoR signalling Staerk, Judith; Defour, Jean-Philippe; Pecquet, Christian The EMBO Journal, Vol. 30, Issue 21 https://doi.org/10.1038/emboj.2011.315	journal	September 2011
Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells Giani, Felix C.; Fiorini, Claudia; Wakabayashi, Aoi Cell Stem Cell, Vol. 18, Issue 1 https://doi.org/10.1016/j.stem.2015.09.015	journal	January 2016
Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes Sockolosky, Jonathan T.; Trotta, Eleonora; Parisi, Giulia Science, Vol. 359, Issue 6379 https://doi.org/10.1126/science.aar3246	journal	March 2018
Will any dimer do? Ballinger, Marcus D.; Wells, James A. Nature Structural Biology, Vol. 5, Issue 11 https://doi.org/10.1038/2911	journal	November 1998
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Crystal Structure of the Marburg Virus VP35 Oligomerization Domain Bruhn, Jessica F.; Kirchdoerfer, Robert N.; Urata, Sarah M. Journal of Virology, Vol. 91, Issue 2 https://doi.org/10.1128/JVI.01085-16	journal	November 2016
Collaboration gets the most out of software Morin, Andrew; Eisenbraun, Ben; Key, Jason eLife, Vol. 2 https://doi.org/10.7554/eLife.01456	journal	September 2013
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo Hu, Jingping; Liu, Jing; Xue, Fumin Blood, Vol. 121, Issue 16 https://doi.org/10.1182/blood-2013-01-476390	journal	April 2013
Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases Akdis, Mübeccel; Aab, Alar; Altunbulakli, Can Journal of Allergy and Clinical Immunology, Vol. 138, Issue 4 https://doi.org/10.1016/j.jaci.2016.06.033	journal	October 2016
Designing Repeat Proteins: Well-expressed, Soluble and Stable Proteins from Combinatorial Libraries of Consensus Ankyrin Repeat Proteins Binz, H. Kaspar; Stumpp, Michael T.; Forrer, Patrik Journal of Molecular Biology, Vol. 332, Issue 2 https://doi.org/10.1016/S0022-2836(03)00896-9	journal	September 2003
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Interpreting mixed signals: the cell's cytokine conundrum Delgoffe, Greg M.; Murray, Peter J.; Vignali, Dario AA Current Opinion in Immunology, Vol. 23, Issue 5 https://doi.org/10.1016/j.coi.2011.07.013	journal	October 2011
Functional Mimicry of a Protein Hormone by a Peptide Agonist: The EPO Receptor Complex at 2.8 A Livnah, O.; Stura, E. A.; Johnson, D. L. Science, Vol. 273, Issue 5274 https://doi.org/10.1126/science.273.5274.464	journal	July 1996
A Reducing and Oxidizing System Minimizes Photobleaching and Blinking of Fluorescent Dyes Vogelsang, Jan; Kasper, Robert; Steinhauer, Christian Angewandte Chemie International Edition, Vol. 47, Issue 29, p. 5465-5469 https://doi.org/10.1002/anie.200801518	journal	July 2008
Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling Wilmes, Stephan; Beutel, Oliver; Li, Zhi The Journal of Cell Biology, Vol. 209, Issue 4 https://doi.org/10.1083/jcb.201412049	journal	May 2015
Effective screening method of agonistic diabodies based on autocrine growth Nakano, Kiyotaka; Kojima, Tetsuo; Kasutani, Keiko Journal of Immunological Methods, Vol. 347, Issue 1-2 https://doi.org/10.1016/j.jim.2009.05.012	journal	August 2009
Cell Signaling by Receptor Tyrosine Kinases Lemmon, Mark A.; Schlessinger, Joseph Cell, Vol. 141, Issue 7 https://doi.org/10.1016/j.cell.2010.06.011	journal	June 2010
Designed Ankyrin Repeat Proteins (DARPins): Binding Proteins for Research, Diagnostics, and Therapy Plückthun, Andreas Annual Review of Pharmacology and Toxicology, Vol. 55, Issue 1 https://doi.org/10.1146/annurev-pharmtox-010611-134654	journal	January 2015
Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling Ho, Chia Chi M.; Chhabra, Akanksha; Starkl, Philipp Cell, Vol. 168, Issue 6 https://doi.org/10.1016/j.cell.2017.02.011	journal	March 2017
Hematopoietic cytokines Metcalf, Donald Blood, Vol. 111, Issue 2 https://doi.org/10.1182/blood-2007-03-079681	journal	January 2008
Recent developments in biased agonism Wisler, James W.; Xiao, Kunhong; Thomsen, Alex RB Current Opinion in Cell Biology, Vol. 27 https://doi.org/10.1016/j.ceb.2013.10.008	journal	April 2014
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
An introduction to data reduction: space-group determination, scaling and intensity statistics Evans, Philip R. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S090744491003982X	journal	March 2011
Ankyrin Repeat: A Unique Motif Mediating Protein−Protein Interactions ^† Li, Junan; Mahajan, Anjali; Tsai, Ming-Daw Biochemistry, Vol. 45, Issue 51 https://doi.org/10.1021/bi062188q	journal	December 2006
The Prolactin Receptor Rescues EpoR−/− Erythroid Progenitors and Replaces EpoR in a Synergistic Interaction With c-kit Socolovsky, Merav; Fallon, Amy E. J.; Lodish, Harvey F. Blood, Vol. 92, Issue 5 https://doi.org/10.1182/blood.V92.5.1491	journal	September 1998
Apoptotic mechanisms in the control of erythropoiesis Testa, U. Leukemia, Vol. 18, Issue 7 https://doi.org/10.1038/sj.leu.2403383	journal	June 2004
Rapid Transfer of Transmembrane Proteins for Single Molecule Dimerization Assays in Polymer-Supported Membranes Roder, Friedrich; Wilmes, Stephan; Richter, Christian P. ACS Chemical Biology, Vol. 9, Issue 11 https://doi.org/10.1021/cb5005806	journal	September 2014
Mechanistic Diversity of Cytokine Receptor Signaling Across Cell Membranes Stroud, R. M.; Wells, J. A. Science Signaling, Vol. 2004, Issue 231 https://doi.org/10.1126/stke.2312004re7	journal	April 2004
Structural Linkage between Ligand Discrimination and Receptor Activation by Type I Interferons Thomas, Christoph; Moraga, Ignacio; Levin, Doron Cell, Vol. 146, Issue 4 https://doi.org/10.1016/j.cell.2011.06.048	journal	August 2011
Interleukin-2 Activity Can Be Fine Tuned with Engineered Receptor Signaling Clamps Mitra, Suman; Ring, Aaron M.; Amarnath, Shoba Immunity, Vol. 42, Issue 5 https://doi.org/10.1016/j.immuni.2015.04.018	journal	May 2015
Computational design of self-assembling cyclic protein homo-oligomers Fallas, Jorge A.; Ueda, George; Sheffler, William Nature Chemistry, Vol. 9, Issue 4 https://doi.org/10.1038/nchem.2673	journal	December 2016
High-affinity binders selected from designed ankyrin repeat protein libraries Binz, H. Kaspar; Amstutz, Patrick; Kohl, Andreas Nature Biotechnology, Vol. 22, Issue 5, p. 575-582 https://doi.org/10.1038/nbt962	journal	April 2004
From DARPins to LoopDARPins: Novel LoopDARPin Design Allows the Selection of Low Picomolar Binders in a Single Round of Ribosome Display Schilling, Johannes; Schöppe, Jendrik; Plückthun, Andreas Journal of Molecular Biology, Vol. 426, Issue 3 https://doi.org/10.1016/j.jmb.2013.10.026	journal	February 2014
Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation Kim, Ah Ram; Ulirsch, Jacob C.; Wilmes, Stephan Cell, Vol. 168, Issue 6 https://doi.org/10.1016/j.cell.2017.02.026	journal	March 2017
Efficiency of signalling through cytokine receptors depends critically on receptor orientation Syed, Rashid S.; Reid, Scott W.; Li, Cuiwei Nature, Vol. 395, Issue 6701 https://doi.org/10.1038/26773	journal	October 1998
EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics Freed, Daniel M.; Bessman, Nicholas J.; Kiyatkin, Anatoly Cell, Vol. 171, Issue 3 https://doi.org/10.1016/j.cell.2017.09.017	journal	October 2017
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard Terwilliger, Thomas C.; Grosse-Kunstleve, Ralf W.; Afonine, Pavel V. Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 1 https://doi.org/10.1107/S090744490705024X	journal	December 2007
Lineage-Specific Hematopoietic Growth Factors Kaushansky, Kenneth New England Journal of Medicine, Vol. 354, Issue 19 https://doi.org/10.1056/NEJMra052706	journal	May 2006
Isolating and engineering human antibodies using yeast surface display Chao, Ginger; Lau, Wai L.; Hackel, Benjamin J. Nature Protocols, Vol. 1, Issue 2 https://doi.org/10.1038/nprot.2006.94	journal	July 2006
Insights into Cytokine–Receptor Interactions from Cytokine Engineering Spangler, Jamie B.; Moraga, Ignacio; Mendoza, Juan L. Annual Review of Immunology, Vol. 33, Issue 1 https://doi.org/10.1146/annurev-immunol-032713-120211	journal	March 2015
Selecting Agonists from Single Cells Infected with Combinatorial Antibody Libraries Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia Chemistry & Biology, Vol. 20, Issue 5 https://doi.org/10.1016/j.chembiol.2013.04.012	journal	May 2013
Dynamic multiple-target tracing to probe spatiotemporal cartography of cell membranes Sergé, Arnauld; Bertaux, Nicolas; Rigneault, Hervé Nature Methods, Vol. 5, Issue 8 https://doi.org/10.1038/nmeth.1233	journal	July 2008
Low-resolution refinement tools in REFMAC 5 Nicholls, Robert A.; Long, Fei; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S090744491105606X	journal	March 2012
Robust single-particle tracking in live-cell time-lapse sequences Jaqaman, Khuloud; Loerke, Dinah; Mettlen, Marcel Nature Methods, Vol. 5, Issue 8 https://doi.org/10.1038/nmeth.1237	journal	July 2008
Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor Kai, Masayuki; Motoki, Kazuhiro; Yoshida, Hideaki Nature Biotechnology, Vol. 26, Issue 2 https://doi.org/10.1038/nbt1376	journal	December 2007
Dimerization of the Erythropoietin Receptor Transmembrane Domain in Micelles Ebie, Alexandra Z.; Fleming, Karen G. Journal of Molecular Biology, Vol. 366, Issue 2 https://doi.org/10.1016/j.jmb.2006.11.035	journal	February 2007
The Erythropoietin Receptor Transmembrane Domain Mediates Complex Formation with Viral Anemic and Polycythemic gp55 Proteins Constantinescu, Stefan N.; Keren, Tzvia; Russ, William P. Journal of Biological Chemistry, Vol. 278, Issue 44 https://doi.org/10.1074/jbc.M302974200	journal	August 2003
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands Moraga, Ignacio; Wernig, Gerlinde; Wilmes, Stephan Cell, Vol. 160, Issue 6 https://doi.org/10.1016/j.cell.2015.02.011	journal	March 2015
Biased ligand quantification in drug discovery: from theory to high throughput screening to identify new biased μ opioid receptor agonists: Identification of new biased μ receptor agonists Winpenny, David; Clark, Mellissa; Cawkill, Darren British Journal of Pharmacology, Vol. 173, Issue 8 https://doi.org/10.1111/bph.13441	journal	March 2016
REFMAC 5 for the refinement of macromolecular crystal structures Murshudov, Garib N.; Skubák, Pavol; Lebedev, Andrey A. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911001314	journal	March 2011
An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway Rowlinson, Scott W.; Yoshizato, Hideo; Barclay, Johanna L. Nature Cell Biology, Vol. 10, Issue 6 https://doi.org/10.1038/ncb1737	journal	May 2008
Automated refinement of macromolecular structures at low resolution using prior information Kovalevskiy, Oleg; Nicholls, Robert A.; Murshudov, Garib N. Acta Crystallographica Section D Structural Biology, Vol. 72, Issue 10 https://doi.org/10.1107/S2059798316014534	journal	September 2016
IL-10 Elicits IFNγ-Dependent Tumor Immune Surveillance Mumm, John B.; Emmerich, Jan; Zhang, Xueqing Cancer Cell, Vol. 20, Issue 6 https://doi.org/10.1016/j.ccr.2011.11.003	journal	December 2011
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER Smart, Oliver S.; Womack, Thomas O.; Flensburg, Claus Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444911056058	journal	March 2012
Library Generation by Gene Shuffling Meyer, Adam J.; Ellefson, Jared W.; Ellington, Andrew D. Current Protocols in Molecular Biology, Vol. 105, Issue 1 https://doi.org/10.1002/0471142727.mb1512s105	journal	January 2014
X-Ray Diffraction data from EpoR complex with monoextended DARPin R12, source of 6MOL structure Jude, Kevin M. SBGrid Data Bank https://doi.org/10.15785/sbgrid/619	dataset	January 2019
X-Ray Diffraction data from EpoR complex with dimeric DARPin ACR5, source of 6MOJ structure Jude, Kevin M. SBGrid Data Bank https://doi.org/10.15785/sbgrid/620	dataset	January 2019
X-Ray Diffraction data from Dimeric E2C Darpin complex with EpoR, source of 6MOH structure Jude, Kevin M. SBGrid Data Bank https://doi.org/10.15785/sbgrid/622	dataset	January 2019
X-Ray Diffraction data from EpoR complex with dimeric DARPin ANR7, source of 6MOK structure Jude, Kevin M. SBGrid Data Bank https://doi.org/10.15785/sbgrid/623	dataset	January 2019
X-Ray Diffraction data from dimeric DARPin E2C, source of 6MOG structure Jude, Kevin M. SBGrid Data Bank https://doi.org/10.15785/sbgrid/624	dataset	January 2019
X-Ray Diffraction data from EpoR complex with E2 DARPin, source of 6MOE structure Jude, Kevin M. SBGrid Data Bank https://doi.org/10.15785/sbgrid/626	dataset	January 2019
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome Sharma, Deepti; De Falco, Louis; Padavattan, Sivaraman Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-13641-0	journal	December 2019
Synthetic antibodies against BRIL as universal fiducial marks for single−particle cryoEM structure determination of membrane proteins Mukherjee, Somnath; Erramilli, Satchal K.; Ammirati, Mark Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-15363-0	journal	March 2020
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
Overview of the CCP4 suite and current developments. Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.52322	text	January 2011
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard. Terwilliger, Thomas C.; Grosse-Kunstleve, Ralf W.; Afonine, Pavel V. International Union of Crystallography (IUCr) https://doi.org/10.17863/cam.52329	journalarticle	January 2008
From DARPins to LoopDARPins: novel LoopDARPin design allows the selection of low picomolar binders in a single round of ribosome display Schilling, Johannes; Schöppe, Jendrik; Plückthun, Andreas Elsevier https://doi.org/10.5167/uzh-96988	text	January 2014
Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy Plückthun, Andreas Annual Reviews https://doi.org/10.5167/uzh-113050	text	January 2015
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases Mübeccel, Akdis,; Alar, Aab,; Can, Altunbulakli, Elsevier https://doi.org/10.5167/uzh-128095	text	January 2016

Cited By (2)

Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations Wilmes, Stephan; Hafer, Maximillian; Vuorio, Joni Zenodo https://doi.org/10.5281/zenodo.3555290	text	January 2019
Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations Wilmes, Stephan; Hafer, Maximillian; Vuorio, Joni Science, Vol. 367, Issue 6478 https://doi.org/10.1126/science.aaw3242	journal	February 2020

Similar Records

Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation

Journal Article · Wed Jul 25 00:00:00 EDT 2018 · eLife · OSTI ID:1532487

Ferrao, Ryan D.; Wallweber, Heidi JA; Lupardus, Patrick J.

Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10

Journal Article · Thu Mar 18 00:00:00 EDT 2021 · Science · OSTI ID:1532487

Saxton, Robert A.; Tsutsumi, Naotaka; Su, Leon L.; +6 more

Packing Density of the Erythropoietin Receptor Transmembrane Domain Correlates with Amplification of Biological Responses

Journal Article · Wed Oct 01 00:00:00 EDT 2008 · Biochemistry (American Chemical Society) · OSTI ID:1532487

Becker, Verena; Sengupta, D; Ketteler, Robin; +3 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Title: Topological control of cytokine receptor signaling induces differential effects in hematopoiesis

Citation Formats

References (73)

Cited By (2)

Similar Records

Related Subjects