Blood, 1 August 2002, Vol. 100, No. 3, pp. 966-973
NEOPLASIA
Functional involvement of Akt signaling downstream of Jak1 in
v-Abl-induced activation of hematopoietic cells
Shinji Oki,
Andre Limnander,
Nika N. Danial, and
Paul B. Rothman
From the Department of Medicine; Integrated Program in
Cellular, Molecular and Biophysical Studies; and Department of
Microbiology; Columbia University College of Physicians and Surgeons,
New York, NY.
Activation of intracellular signaling pathways is important for
cellular transformation and tumorigenesis. The nonreceptor tyrosine
kinases Jak1 and Jak3, which bind to the v-Abl oncoprotein, are
constitutively activated in cells transformed with the Abelson murine
leukemia virus. A mutant of p160 v-Abl lacking the Jak1-binding region
(v-Abl 
858-1080) has a significant defect in Jak/STAT (signal
transducers and activators of transcription) activation, cytokine-independent cell growth/survival, and tumorigenesis. To
identify the pathways downstream of Jak kinases in v-Abl-mediated signaling, we examined the activation of several signaling molecules by
p160 v-Abl or the v-Abl 858-1080 mutant. We demonstrate that, in
addition to the decreased Ras activation, signaling through phosphatidylinositol-3 kinase and Akt are impaired in cells expressing mutant v-Abl. The proliferative defect of v-Abl 858-1080 was rescued
by activated v-Akt and was also moderately rescued by activated
v-H-Ras. However, constitutive active phosphatidylinositol-3 kinase
(p110CAAX) did not complement this effect. Cells expressing v-Abl
858-1080 demonstrated reduced tumor formation in nude mice. In
contrast, cells coexpressing v-Akt with v-Abl 858-1080 demonstrated reduced latency and increased frequency of tumor formation in nude nice
compared with cells expressing v-Abl 858-1080 alone, whereas v-H-Ras
or p110CAAX had minimum effects on tumor formation. These results
suggest that Jak1-dependent Akt activation is important in
v-Abl-mediated transformation.
