Functional involvement of Akt signaling downstream of Jak1 in v-Abl-induced activation of hematopoietic cells.
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 Delta858-1080) 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 Delta858-1080 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 Delta858-1080 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 Delta858-1080 demonstrated reduced tumor formation in nude mice. In contrast, cells coexpressing v-Akt with v-Abl Delta858-1080 demonstrated reduced latency and increased frequency of tumor formation in nude nice compared with cells expressing v-Abl Delta858-1080 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.
Oki
Shinji
S
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032-3702, USA.
Limnander
Andre
A
Danial
Nika N
NN
Rothman
Paul B
PB
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D053613:Janus Kinase 1; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D016374:Oncogene Proteins v-abl / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D020239:Receptor Cross-Talk; D017384:Sequence Deletion; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D053613:Janus Kinase 1; D016374:Oncogene Proteins v-abl; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; C507905:Jak1 protein, mouse