title: Orientation-specific signalling by thrombopoietin receptor dimers.
abstract: Ligand binding to the thrombopoietin receptor is thought to stabilize an active receptor dimer that regulates megakaryocyte differentiation and platelet formation, as well as haematopoietic stem cell renewal. By fusing a dimeric coiled coil in all seven possible orientations to the thrombopoietin receptor transmembrane (TM)-cytoplasmic domains, we show that specific biological effects and in vivo phenotypes are imparted by distinct dimeric orientations, which can be visualized by cysteine mutagenesis and crosslinking. Using functional assays and computational searches, we identify one orientation that represents the inactive dimeric state and another similar to a physiologically activated receptor. Several other dimeric orientations are identified that induce proliferation and in vivo myeloproliferative and myelodysplastic disorders, indicating the receptor can signal from several dimeric interfaces. The set of dimeric thrombopoietin receptors with different TM orientations may offer new insights into the activation of distinct signalling pathways by a single receptor and suggests that subtle differences in cytokine receptor dimerization provide a new layer of signalling regulation that is relevant for disease.
authors: Ludwig Institute for Cancer Research, Brussels, Belgium.
authors: Judith
authors: J
authors: Staerk
authors: Jean-Philippe
authors: JP
authors: Defour
authors: Christian
authors: C
authors: Pecquet
authors: Emilie
authors: E
authors: Leroy
authors: Hélène
authors: H
authors: Antoine-Poirel
authors: Ian
authors: I
authors: Brett
authors: Miki
authors: M
authors: Itaya
authors: Steven O
authors: SO
authors: Smith
authors: William
authors: W
authors: Vainchenker
authors: Stefan N
authors: SN
authors: Constantinescu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000502:physiology; D060066:Protein Interaction Maps; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology*; D053628:Receptors, Thrombopoietin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013237:Stereoisomerism
chemical_list: D053628:Receptors, Thrombopoietin