Socs-1 inhibits TEL-JAK2-mediated transformation of hematopoietic cells through inhibition of JAK2 kinase activity and induction of proteasome-mediated degradation.
TEL-JAK2 fusion proteins, which are a result of t(9;12)(p24;p13) translocations associated with human leukemia, activate Stat5 in vitro and in vivo and cause a myelo- and lymphoproliferative disease in a murine bone marrow transplant model. We report that Socs-1, a member of the SOCS family of endogenous inhibitors of JAKs and STATs, inhibits transformation of Ba/F3 cells by TEL-JAK2 but has no effect on Ba/F3 cells transformed by BCR-ABL, TEL-ABL, or TEL-platelet-derived growth factor receptor beta. TEL-JAK2, in addition to activating Stat5, associates with Shc and Grb2 and induces activation of Erk2, and expression of Socs-1 inhibits engagement of each of these signaling molecules. TEL-JAK2 kinase activity is inhibited by Socs-1, as assessed by in vitro kinase assays. In addition, Socs-1 induces proteasomal degradation of TEL-JAK2. Mutational analysis indicates that the SOCS box of Socs-1 is required for proteasomal degradation and for abrogation of growth of TEL-JAK2-transformed cells. Furthermore, murine bone marrow transplant assays demonstrate that expression of Socs-1 prolongs latency of TEL-JAK2-mediated disease in vivo. Collectively, these data indicate that Socs-1 inhibits TEL-JAK2 in vitro and in vivo through inhibition of kinase activity and induction of TEL-JAK2 protein degradation.
Frantsve
J
J
Division of Hematology, Department of Medicine, Boston, Massachusetts 02115.
Schwaller
J
J
Sternberg
D W
DW
Kutok
J
J
Gilliland
D G
DG
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004789:Enzyme Activation; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology*; D053614:Janus Kinase 2; D051379:Mice; D009097:Multienzyme Complexes / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000097764:ETS Translocation Variant 6 Protein
D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D053614:Janus Kinase 2; D009097:Multienzyme Complexes; D015514:Oncogene Proteins, Fusion; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C491590:Socs1 protein, mouse; C108603:TEL-JAK2 fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C491568:TEL-JAK2 fusion protein, mouse; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse