P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members.
The products of the Philadelphia chromosome translocation, P210 and P190(BCR/ABL), are cytoplasmic protein tyrosine kinases that share the ability to transform hematopoietic cytokine-dependent cell lines to cytokine independence but differ in the spectrum of leukemia induced in vivo. We have analyzed the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways in hematopoietic cells transformed by Bcr/Abl. STAT5 and, to a lesser extent, STATs 1 and 3 were constitutively activated by tyrosine phosphorylation and induction of DNA binding activity in both P210 and P190(BCR/ABL)-transformed cells, but P190 differed in that it also prominently activated STAT6. There was low level tyrosine phosphorylation of JAKs 1, 2, and 3 in Bcr/Abl-transformed cells, but no detectable complex formation with Bcr/Abl, and activation of STAT5 by P210 was not blocked by two different dominant-negative JAK mutants. These results suggest that P210 and P190(BCR/ABL) directly activate specific STAT family members and may help explain their overlapping yet distinct roles in leukemogenesis.
Ilaria
R L
RL
Division of Hematology/Oncology, Department of Medicine, Brigham and Women's Hospital, Massachusetts 02115, USA.
Van Etten
R A
RA
D002461:Cell Line, Transformed; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D008894:Milk Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D014443:Tyrosine; D004247:DNA; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3