Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation

DC ElementWertSprache
dc.contributor.authorKim, Ah Ram
dc.contributor.authorUlirsch, Jacob C.
dc.contributor.authorWilmes, Stephan
dc.contributor.authorUnal, Ekrem
dc.contributor.authorMoraga, Ignacio
dc.contributor.authorKarakukcu, Musa
dc.contributor.authorYuan, Daniel
dc.contributor.authorKazerounian, Shideh
dc.contributor.authorAbdulhay, Nour J.
dc.contributor.authorKing, David S.
dc.contributor.authorGupta, Namrata
dc.contributor.authorGabriel, Stacey B.
dc.contributor.authorLander, Eric S.
dc.contributor.authorPatiroglu, Turkan
dc.contributor.authorOzcan, Alper
dc.contributor.authorOzdemir, Mehmet Akif
dc.contributor.authorGarcia, K. Christopher
dc.contributor.authorPiehler, Jacob
dc.contributor.authorGazda, Hanna T.
dc.contributor.authorKlein, Daryl E.
dc.contributor.authorSankaran, Vijay G.
dc.date.accessioned2021-12-23T16:23:52Z-
dc.date.available2021-12-23T16:23:52Z-
dc.date.issued2017
dc.identifier.issn00928674
dc.identifier.urihttps://osnascholar.ub.uni-osnabrueck.de/handle/unios/14694-
dc.description.abstractCytokines 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.sponsorshipNIHUnited 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.isoen
dc.publisherCELL PRESS
dc.relation.ispartofCELL
dc.subjectBIASED AGONISM
dc.subjectBiochemistry & Molecular Biology
dc.subjectCell Biology
dc.subjectDIAMOND-BLACKFAN ANEMIA
dc.subjectERYTHROPOIETIN RECEPTOR
dc.subjectGENETIC-VARIATION
dc.subjectIDENTIFICATION
dc.subjectINHIBITOR
dc.subjectMYELOPROLIFERATIVE NEOPLASMS
dc.subjectPHOSPHATASE
dc.subjectPROTEINS
dc.subjectTYROSINE
dc.titleFunctional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation
dc.typejournal article
dc.identifier.doi10.1016/j.cell.2017.02.026
dc.identifier.isiISI:000396287900013
dc.description.volume168
dc.description.issue6
dc.description.startpage1053+
dc.contributor.orcid0000-0003-2015-3541
dc.contributor.orcid0000-0001-9909-0701
dc.contributor.orcid0000-0002-7188-0450
dc.contributor.orcid0000-0002-4112-710X
dc.contributor.orcid0000-0002-2691-4826
dc.contributor.orcid0000-0002-7947-0827
dc.contributor.orcid0000-0002-2794-3776
dc.contributor.orcid0000-0002-6100-1205
dc.contributor.researcheridAAT-4574-2021
dc.contributor.researcheridA-5099-2019
dc.identifier.eissn10974172
dc.publisher.place600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
dcterms.isPartOf.abbreviationCell
dcterms.oaStatusGreen Accepted, Bronze
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptidfb05-
crisitem.author.orcid0000-0002-2143-2270-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.netidPiJa938-
Zur Kurzanzeige

Seitenaufrufe

2
Letzte Woche
0
Letzter Monat
0
geprüft am 15.05.2024

Google ScholarTM

Prüfen

Altmetric