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Molecular and Cellular Biology, May 2001, p. 3547-3557, Vol. 21, No. 10
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.10.3547-3557.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Socs-1 Inhibits TEL-JAK2-Mediated Transformation of Hematopoietic Cells through Inhibition of JAK2 Kinase Activity and Induction of Proteasome-Mediated Degradation

Julie Frantsve,1,2 Juerg Schwaller,1,dagger David W. Sternberg,1 Jeffery Kutok,3 and D. Gary Gilliland1,2,4,*

Division of Hematology, Department of Medicine,1 and Department of Pathology,3 Brigham and Women's Hospital, Harvard Institutes of Medicine, Harvard Medical School,2 and Howard Hughes Medical Institute,4 Boston, Massachusetts 02115

Received 1 December 2000/Returned for modification 10 January 2001/Accepted 22 February 2001

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.

* Corresponding author. Mailing address: Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115. Phone: (617) 525-5525. Fax: (617) 525-5530. E-mail: gilliland{at}calvin.bwh.harvard.edu.

dagger Present address: Institute de Pathologie Clinique, Hôpital Cantonale Univérsitaire de Genève, Geneva, Switzerland.

Molecular and Cellular Biology, May 2001, p. 3547-3557, Vol. 21, No. 10
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.10.3547-3557.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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