Evidence map›Paper›PMID 28283061›Full record

ArticleCell2017

Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation.

Ah Ram Kim, Jacob C Ulirsch, Stephan Wilmes, Ekrem Unal, Ignacio Moraga, Musa Karakukcu, Daniel Yuan, Shideh Kazerounian, Nour J Abdulhay, David S King and 11 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.

0numbers the graph read from it
0cells of the map it votes in
76citing papers in PubMed
6.7field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

76 citing papers in PubMed, 117 citations in OpenAlex.

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  12. Rare penetrant mutations confer severe risk of common diseases.medRxiv : the preprint server for health sciences · 2023
    Article
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16 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors at 10 institutions in 3 countries.

Ah Ram KimDivision of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jacob C UlirschDivision of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Stephan WilmesDepartment of Biology, Division of Biophysics, University of Osnabrück, 49076 Osnabrück, Germany.
Ekrem UnalDepartment of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri 38039, Turkey.
Ignacio MoragaDepartment of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Musa KarakukcuDepartment of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri 38039, Turkey.
Daniel YuanDivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Shideh KazerounianDivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Nour J AbdulhayDivision of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
David S KingHoward Hughes Medical Institute Mass Spectrometry Laboratory, University of California Berkeley, Berkeley, CA 94720, USA.
Namrata GuptaBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Stacey B GabrielBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Eric S LanderBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Turkan PatirogluDepartment of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri 38039, Turkey.
Alper OzcanDepartment of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri 38039, Turkey.
Mehmet Akif OzdemirDepartment of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri 38039, Turkey.
K Christopher GarciaDepartment of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jacob PiehlerDepartment of Biology, Division of Biophysics, University of Osnabrück, 49076 Osnabrück, Germany.
Hanna T GazdaBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Daryl E KleinDepartment of Pharmacology, Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA. Electronic address: daryl.klein@yale.edu.
Vijay G SankaranDivision of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: sankaran@broadinstitute.org.
Erciyes University · TRBroad Institute · USDana-Farber Cancer Institute · USOsnabrück University · DEStanford University · USBoston Children's Hospital · USDana-Farber/Boston Children's Cancer and Blood Disorders Center · USHarvard University · USUniversity of California, Berkeley · USYale University · US

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
Systematic Genetic Dissection of Human ErythropoiesisR01DK103794 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI Vijay Ganesh Sankaran · 2014 to 2026
$5.9M
Structure, function and engineering of immune cytokine receptor signalingR37AI051321 · NIAID · STANFORD UNIVERSITY · PI GARCIA, KENAN CHRISTOPHER · 2013 to 2022
$4.2M
Identifying Genome-wide Association Study-Nominated Regulators of ErythropoiesisR33HL120791 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI SANKARAN, VIJAY GANESH · 2016 to 2018
$1.7M
New gene discoveries and biology of ribosomes in Diamond-Blackfan anemia.R01HL107558 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI GAZDA, HANNA TERESA · 2011 to 2014
$1.6M
New Gene Discoveries and Biology of Ribosomes in Diamond-Blackfan AnemiaK02HL111156 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI GAZDA, HANNA TERESA · 2012 to 2016
$568k
NHGRI NIH HHS U54 HG003067NHLBI NIH HHS K02 HL111156NHLBI NIH HHS R01 HL107558NHLBI NIH HHS R33 HL120791NIAID NIH HHS R37 AI051321NIDDK NIH HHS R01 DK103794
6 · The paper itself

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.

Indexed as

Mutation, MissenseSignal TransductionAnemia, Diamond-BlackfanChildConsanguinityEnzyme ActivationErythropoiesisErythropoietinFemaleHumansJanus Kinase 2KineticsMaleReceptors, ErythropoietinEPO protein, humanErythropoietinJAK2 protein, humanJanus Kinase 2Receptors, Erythropoietincytokineerythropoiesiserythropoietinfunctional selectivityhematopoiesisJAK2receptorsignaling

Identifiers

PMID28283061
PMCPMC5376096
OpenAlexW2594357415

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.