TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways.
We previously reported the fusion of the TEL gene to the Syk gene in myelodysplastic syndrome with t(9;12)(q22;p12). TEL-Syk fusion transformed interleukin-3 (IL-3)-dependent murine hematopoietic cell line BaF3 to growth factor independence. Here, we investigate the intracellular signal transduction of the stable transfectants. TEL-Syk fusion protein was associated with the p85 subunit of phosphatidyl inositol 3 kinase (PI3-K) followed by the activation of Akt in the absence of IL-3. Vav, phospholipase C-gamma2 and mitogen-activated protein kinase (MAPK) were also constitutively activated. TEL-Syk also activated the signal transducer and activator of transcription 5 (STAT5) in the absence of Janus kinase 2 activation. None of these kinases were phosphorylated in the BaF3 cells transfected with TELDeltaPNT-Syk in which the oligomerization domain of TEL was deleted. Inhibitor analysis showed that the MAPK pathway was important in TEL-Syk-mediated cell proliferation. The immunofluorescence technique revealed that the TEL-Syk fusion protein was located in the cytoplasm. These data suggest that TEL-Syk fusion protein in the cytoplasm leads to the constitutive activation of PI3-K/Akt, MAPK and STAT5 signal pathways, which are closely involved in IL-3-independent cell proliferation of BaF3 cells.
Kanie
T
T
Department of Hematology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Abe
A
A
Matsuda
T
T
Kuno
Y
Y
Towatari
M
M
Yamamoto
T
T
Saito
H
H
Emi
N
N
Naoe
T
T
D019943:Amino Acid Substitution; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D007700:Kinetics; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D000072377:Syk Kinase; D015534:Trans-Activators; D000097764:ETS Translocation Variant 6 Protein; C507924:JAK2 protein, human; C000606896:SYK protein, human; C494918:AKT1 protein, human