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Janus kinases affect thrombopoietin receptor cell surface localization and stability.

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Royer, Yohan [UCL] Staerk, Judith [UCL] Costuleanu, Marcel [UCL] Courtoy, Pierre J. [UCL] Constantinescu, Stefan N. [UCL]

The thrombopoietin receptor (TpoR) regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation. TpoR signals by activating Janus kinases JAK2 and Tyk2. Here we show that, in addition to signaling downstream from the activated TpoR, JAK2 and Tyk2 strongly promote cell surface localization and enhance total protein levels of the TpoR. This effect is caused by stabilization of the mature endoglycosidase H-resistant form of the receptor. Confocal microscopy indicates that TpoR colocalizes partially with recycling transferrin in Ba/F3 cells. The interaction with JAK2 or Tyk2 appears to protect the receptor from proteasome degradation. Sequences encompassing Box1 and Box2 regions of the receptor cytosolic domain and an intact JAK2 or Tyk2 FERM domain are required for these effects. We discuss the relevance of our results to the reported defects of TpoR processing in myeloproliferative diseases and to the mechanisms of Tpo signaling and clearance via the TpoR.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2005
Journal information "The Journal of biological chemistry" - Vol. 280, no. 29, p. 27251-61 (2005)
Peer reviewed yes
issn 0021-9258
Publication status Publié
Affiliations UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique
UCL - MD/BICL - Département de biochimie et de biologie cellulaire
MESH Subject Animals ; Binding Sites ; Cell Line ; Humans ; Janus Kinase 1 ; Janus Kinase 2 ; Janus Kinase 3 ; Membrane Proteins - metabolism ; Mice ; Oncogene Proteins - chemistry - metabolism ; Proteasome Endopeptidase Complex - metabolism ; Protein-Tyrosine Kinases - metabolism - physiology ; Proto-Oncogene Proteins ; Receptors, Cytokine - chemistry - metabolism ; Receptors, Thrombopoietin ; TYK2 Kinase ; Transfection ; Transferrin - metabolism ; Up-Regulation
Links
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Bibliographic reference Royer, Yohan ; Staerk, Judith ; Costuleanu, Marcel ; Courtoy, Pierre J. ; Constantinescu, Stefan N.. Janus kinases affect thrombopoietin receptor cell surface localization and stability.. In: The Journal of biological chemistry, Vol. 280, no. 29, p. 27251-61 (2005)
Permanent URL http://hdl.handle.net/2078.1/25896