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 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.
Integrated Program in Molecular, Cellular, and Biophysical Studies, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
N N
NN
Danial
J A
JA
Losman
T
T
Lu
N
N
Yip
K
K
Krishnan
J
J
Krolewski
S P
SP
Goff
J Y
JY
Wang
P B
PB
Rothman
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics; D007377:Interleukin-3 / Q000502:physiology*; D053613:Janus Kinase 1; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D016374:Oncogene Proteins v-abl / Q000737:chemistry*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection / Q000235:genetics
D007377:Interleukin-3; D016374:Oncogene Proteins v-abl; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1