The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells.
Signal transducer and activator of transcription 5 (STAT5) is constitutively activated by BCR/ABL, the oncogenic tyrosine kinase responsible for chronic myelogenous leukemia. The mechanism of BCR/ABL-mediated STAT5 activation is unknown. We show here that the BCR/ABL SH3 and SH2 domains interact with hematopoietic cell kinase (Hck), leading to the stimulation of Hck catalytic activity. Active Hck phosphorylated STAT5B on Tyr699, which represents an essential step in STAT5B stimulation. Moreover, a kinase-dead Hck mutant and Hck inhibitor PP2 abrogated BCR/ABL-dependent activation of STAT5 and elevation of expression of STAT5 downstream effectors A1 and pim-1. These data identify a novel BCR/ABL-Hck-STAT5 signaling pathway, which plays an important role in BCR/ABL-mediated transformation of myeloid cells.
Klejman
Agata
A
Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Schreiner
Steven J
SJ
Nieborowska-Skorska
Malgorzata
M
Slupianek
Artur
A
Wilson
Matthew
M
Smithgall
Thomas E
TE
Skorski
Tomasz
T
D000818:Animals; D002384:Catalysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008894:Milk Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C496631:HCK protein, human; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck