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Molecular and Cellular Biology, November 1998, p. 6795-6804, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Direct Interaction of Jak1 and v-Abl Is Required for v-Abl-Induced Activation of STATs and Proliferation

Nika N. Danial,1 Julie A. Losman,1 Tianhong Lu,2 Natalie Yip,2 Kartik Krishnan,3 John Krolewski,3 Stephen P. Goff,4,5,6 Jean Y. J. Wang,7 and Paul B. Rothman1,2,4,*

Integrated Program in Molecular, Cellular, and Biophysical Studies,1 Departments of Medicine,2 Microbiology,4 Biochemistry and Molecular Biophysics,5 and Pathology,3 and Howard Hughes Medical Institute,6 Columbia University College of Physicians and Surgeons, New York, New York 10032, and Department of Biology and Center for Molecular Genetics, University of California at San Diego, La Jolla, California 92093-03477

Received 4 February 1998/Returned for modification 30 March 1998/Accepted 23 July 1998

In Abelson murine leukemia virus (A-MuLV)-transformed cells, members of the Janus kinase (Jak) family of non-receptor tyrosine kinases and the signal transducers and activators of transcription (STAT) family of signaling proteins are constitutively activated. In these cells, the v-Abl oncoprotein and the Jak proteins physically associate. To define the molecular mechanism of constitutive Jak-STAT signaling in these cells, the functional significance of the v-Abl-Jak association was examined. Mapping the Jak1 interaction domain in v-Abl demonstrates that amino acids 858 to 1080 within the carboxyl-terminal region of v-Abl bind Jak1 through a direct interaction. A mutant of v-Abl lacking this region exhibits a significant defect in Jak1 binding in vivo, fails to activate Jak1 and STAT proteins, and does not support either the proliferation or the survival of BAF/3 cells in the absence of cytokine. Cells expressing this v-Abl mutant show extended latency and decreased frequency in generating tumors in nude mice. In addition, inducible expression of a kinase-inactive mutant of Jak1 protein inhibits the ability of v-Abl to activate STATs and to induce cytokine-independent proliferation, indicating that an active Jak1 is required for these v-Abl-induced signaling pathways in vivo. We propose that Jak1 is a mediator of v-Abl-induced STAT activation and v-Abl induced proliferation in BAF/3 cells, and may be important for efficient transformation of immature B cells by the v-abl oncogene.

* Corresponding author. Mailing address: Department of Medicine/Microbiology, Columbia University, 630 W. 168th St., New York, NY 10032-3702. Phone: (212) 305-6982. Fax: (212) 205-1870. E-mail: pbr3{at}columbia.edu.

Molecular and Cellular Biology, November 1998, p. 6795-6804, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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