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J. Biol. Chem., Vol. 280, Issue 29, 27251-27261, July 22, 2005

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Janus Kinases Affect Thrombopoietin Receptor Cell Surface Localization and Stability^*

Yohan Royer, Judith Staerk, Marcel Costuleanu¶, Pierre J. Courtoy, and Stefan N. Constantinescu||

From the Ludwig Institute for Cancer Research, Brussels B-1200, and the Christian de Duve Institute of Cellular Pathology, MEXP and CELL Units, Université de Louvain, Brussels B-1200, Belgium

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.

Received for publication, February 7, 2005 , and in revised form, May 12, 2005.

^* This work was supported by an aspirant Fonds National de la Recherche Scientifique (F.N.R.S.) fellowship (to Y. R.), a Daimler Benz Ph.D. fellowship (to J. S.), and by grants from the Fédération Belge contre le Cancer, the F.N.R.S., and the de Hovre Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Permanent address: Faculty of Dentistry, Medicine, and Pharmacy Gr. T. Popa University, Iasi RO-700115, Romania.

^|| Research associate of the Fonds National de la Recherche Scientifique Belgium. To whom correspondence should be addressed: Ludwig Institute for Cancer Research, Ave. Hippocrate 74, UCL 74.59, Brussels B-1200, Belgium. Tel.: 32-2-764-7540; Fax: 32-2-764-6566; E-mail: stefan.constantinescu{at}bru.licr.org.

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