Janus kinases affect thrombopoietin receptor cell surface localization and stability.
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.
Royer
Yohan
Y
Ludwig Institute for Cancer Research, Brussels B-1200, Belgium.
Staerk
Judith
J
Costuleanu
Marcel
M
Courtoy
Pierre J
PJ
Constantinescu
Stefan N
SN
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine / Q000737:chemistry / Q000378:metabolism*; D053628:Receptors, Thrombopoietin; D053634:TYK2 Kinase; D014162:Transfection; D014168:Transferrin / Q000378:metabolism; D015854:Up-Regulation
D008565:Membrane Proteins; C481270:Mpl protein, mouse; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D014168:Transferrin; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse; D046988:Proteasome Endopeptidase Complex