Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation

Cell. 2017 Mar 9;168(6):1053-1064.e15. doi: 10.1016/j.cell.2017.02.026.

Ah Ram Kim ¹, Jacob C Ulirsch ¹, Stephan Wilmes ², Ekrem Unal ³, Ignacio Moraga ⁴, Musa Karakukcu ³, Daniel Yuan ⁵, Shideh Kazerounian ⁵, Nour J Abdulhay ¹, David S King ⁶, Namrata Gupta ⁷, Stacey B Gabriel ⁷, Eric S Lander ⁷, Turkan Patiroglu ³, Alper Ozcan ³, Mehmet Akif Ozdemir ³, K Christopher Garcia ⁴, Jacob Piehler ², Hanna T Gazda ⁸, Daryl E Klein ⁹, Vijay G Sankaran ¹⁰

Affiliations

1 Division 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.
2 Department of Biology, Division of Biophysics, University of Osnabrück, 49076 Osnabrück, Germany.
3 Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri 38039, Turkey.
4 Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
5 Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
6 Howard Hughes Medical Institute Mass Spectrometry Laboratory, University of California Berkeley, Berkeley, CA 94720, USA.
7 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
8 Broad 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.
9 Department of Pharmacology, Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA. Electronic address: daryl.klein@yale.edu.
10 Division 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.

PMID: 28283061 DOI: 10.1016/j.cell.2017.02.026

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.

Keywords

JAK2; cytokine; erythropoiesis; erythropoietin; functional selectivity; hematopoiesis; receptor; signaling.

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