DIRECT INTERACTION OF JAK1 AND V-ABL IS REQUIRED FOR V-ABL-INDUCED ACTIVATION OF STATS AND PROLIFERATION

In Abelson murine leukemia virus (A-MuLV)-transformed cells, members o f the Janus kinase (Jak) family of non-receptor tyrosine kinases and t he 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 c ells, the functional significance of the v-Abl-Jak association was exa mined. Mapping the Jak1 interaction domain in v-Abl demonstrates that amino acids 858 to 1080 within the carboxyl-terminal region of v-Abl b ind 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 prol iferation or the survival of BAF/3 cells in the absence of cytokine. C ells expressing this v-Abl mutant show extended latency and decreased frequency in generating tumors in nude mice, In addition, inducible ex pression of a kinase-inactive mutant of Jak1 protein inhibits the abil ity of v-Abl to activate STATs and to induce cytokine-independent prol iferation, 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 B AF/3 cells, and may be important for efficient transformation of immat ure B cells by the v-abl oncogene.