JAK-STAT signaling activated by Abl oncogenes.
The Abl oncoproteins v-Abl and BCR-Abl can activate member of the signal transducers and activators of transcription (STAT) family of signaling proteins. The mechanisms by which these oncoproteins activate STATs appear to differ. In cells transformed by v-Abl, Janus kinase (JAK) tyrosine kinases are constitutively activated. In these cells, the v-Abl oncoprotein and the JAK kinases physically associate. Mapping of the JAK interaction domain in v-Abl demonstrates that amino acids within the carboxyl terminal region of v-Abl bind JAKs through a direct interaction. A mutant of v-Abl lacking this region does not bind or activate JAK 1 in vivo, fails to activate STAT proteins, does not induce cellular proliferation, and is less efficient in cellular transformation. Kinase inactive mutants of JAK 1 inhibit the ability of v-Abl to activate STATs, to induce cytokine-independent proliferation, and to transform bone marrow cells. Interestingly, these effects correlate with defects in the activation of several pathways by v-Abl including Akt, PI3-kinase, STATs, and Ras. These data suggest that Jak kinases may play an important role in v-Abl induced transformation. Oncogene (2000).
Danial
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Department of Microbiology, Integrated Program in Molecular, Cellular and Biophysical Studies, College of Physicians and Surgeons of Columbia University, 630 168th Street West, New York, NY 10032, USA.
Rothman
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D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D016313:Genes, abl / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053613:Janus Kinase 1; D016374:Oncogene Proteins v-abl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D016374:Oncogene Proteins v-abl; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D016315:Proto-Oncogene Proteins c-abl