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

Cell
Authors
Keywords
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.

Year of Publication
2017
Journal
Cell
Volume
168
Issue
6
Pages
1053-1064.e15
Date Published
2017 Mar 09
ISSN
1097-4172
DOI
10.1016/j.cell.2017.02.026
PubMed ID
28283061
PubMed Central ID
PMC5376096
Links
Grant list
R01 HL107558 / HL / NHLBI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
K02 HL111156 / HL / NHLBI NIH HHS / United States
R37 AI051321 / AI / NIAID NIH HHS / United States
R33 HL120791 / HL / NHLBI NIH HHS / United States
R01 DK103794 / DK / NIDDK NIH HHS / United States
Additional Materials