Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation
DC Element | Wert | Sprache |
---|---|---|
dc.contributor.author | Kim, Ah Ram | |
dc.contributor.author | Ulirsch, Jacob C. | |
dc.contributor.author | Wilmes, Stephan | |
dc.contributor.author | Unal, Ekrem | |
dc.contributor.author | Moraga, Ignacio | |
dc.contributor.author | Karakukcu, Musa | |
dc.contributor.author | Yuan, Daniel | |
dc.contributor.author | Kazerounian, Shideh | |
dc.contributor.author | Abdulhay, Nour J. | |
dc.contributor.author | King, David S. | |
dc.contributor.author | Gupta, Namrata | |
dc.contributor.author | Gabriel, Stacey B. | |
dc.contributor.author | Lander, Eric S. | |
dc.contributor.author | Patiroglu, Turkan | |
dc.contributor.author | Ozcan, Alper | |
dc.contributor.author | Ozdemir, Mehmet Akif | |
dc.contributor.author | Garcia, K. Christopher | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Gazda, Hanna T. | |
dc.contributor.author | Klein, Daryl E. | |
dc.contributor.author | Sankaran, Vijay G. | |
dc.date.accessioned | 2021-12-23T16:23:52Z | - |
dc.date.available | 2021-12-23T16:23:52Z | - |
dc.date.issued | 2017 | |
dc.identifier.issn | 00928674 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14694 | - |
dc.description.abstract | Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies. | |
dc.description.sponsorship | NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01DK103794, R33HL120791, R01HL107558, K02HL111156, U54HG003067]; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [K02HL111156, R01HL107558, R33HL120791] Funding Source: NIH RePORTER; NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [U54HG003067] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R37AI051321] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK103794] Funding Source: NIH RePORTER; We are grateful to the family described in this paper for their willingness to participate in this study. We thank M. Lemmon, S. Harrison, H. Lodish, F. Bunn, J. Casanova, D. Nathan, S. Orkin, D. Ginsburg, and members of the Sankaran laboratory for valuable comments and advice on this work. We thank S. Ozcan for assistance with aspirate imaging. This work was funded by NIH grants R01DK103794 and R33HL120791 (V.G.S.), R01HL107558 and K02HL111156 (H.T.G), and U54HG003067 (S.B.G. and E.S.L.). | |
dc.language.iso | en | |
dc.publisher | CELL PRESS | |
dc.relation.ispartof | CELL | |
dc.subject | BIASED AGONISM | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | Cell Biology | |
dc.subject | DIAMOND-BLACKFAN ANEMIA | |
dc.subject | ERYTHROPOIETIN RECEPTOR | |
dc.subject | GENETIC-VARIATION | |
dc.subject | IDENTIFICATION | |
dc.subject | INHIBITOR | |
dc.subject | MYELOPROLIFERATIVE NEOPLASMS | |
dc.subject | PHOSPHATASE | |
dc.subject | PROTEINS | |
dc.subject | TYROSINE | |
dc.title | Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation | |
dc.type | journal article | |
dc.identifier.doi | 10.1016/j.cell.2017.02.026 | |
dc.identifier.isi | ISI:000396287900013 | |
dc.description.volume | 168 | |
dc.description.issue | 6 | |
dc.description.startpage | 1053+ | |
dc.contributor.orcid | 0000-0003-2015-3541 | |
dc.contributor.orcid | 0000-0001-9909-0701 | |
dc.contributor.orcid | 0000-0002-7188-0450 | |
dc.contributor.orcid | 0000-0002-4112-710X | |
dc.contributor.orcid | 0000-0002-2691-4826 | |
dc.contributor.orcid | 0000-0002-7947-0827 | |
dc.contributor.orcid | 0000-0002-2794-3776 | |
dc.contributor.orcid | 0000-0002-6100-1205 | |
dc.contributor.researcherid | AAT-4574-2021 | |
dc.contributor.researcherid | A-5099-2019 | |
dc.identifier.eissn | 10974172 | |
dc.publisher.place | 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA | |
dcterms.isPartOf.abbreviation | Cell | |
dcterms.oaStatus | Green Accepted, Bronze | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.orcid | 0000-0002-2143-2270 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | PiJa938 | - |
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geprüft am 15.05.2024