Characterization of the chronic myelomonocytic leukemia associated TEL-PDGF beta R fusion protein.
The t(5;12) translocation, associated with chronic myelomonocytic leukemia, generates a novel gene encoding a protein, TEL-PDGF beta R, composed of the 154 amino-terminal amino acids of the transcription factor TEL and the transmembrane and intracellular part of the PDGF beta-receptor (PDGF beta R). TEL also occurs as a tumor-associated fusion partner for the tyrosine kinases c-ABL, JAK2 and TRK-C. Previous studies have demonstrated growth promoting activity of TEL-PDGF beta R and also indicated that the TEL moiety activates the tyrosine kinase of the PDGF beta R through the formation of TEL-PDGF beta R oligomers. We demonstrate that tyrosine phosphorylation of the fusion protein can be attenuated through overexpression of the TEL part of TEL-PDGF beta R, suggesting a strategy for antagonizing the signaling of TEL-PDGF beta R, and other TEL-fusion proteins containing tyrosine kinase domains. Comparison of BaF/3 cell lines expressing TEL-PDGF beta R and ligand-stimulated PDGF beta R revealed that only TEL-PDGF beta R expression conferred IL-3-independent growth, suggesting differences in signaling capacity of the two proteins. Finally, tyrosine residues 17 and 27 in TEL-PDGF beta R was identified as autophosphorylation sites in TEL-PDGF beta R.
Sjöblom
T
T
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Boureux
A
A
Rönnstrand
L
L
Heldin
C H
CH
Ghysdael
J
J
Ostman
A
A
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017931:DNA Primers; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010649:Phenylalanine / Q000235:genetics; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D008024:Ligands; D015514:Oncogene Proteins, Fusion; C120888:TEL-PDGFRbeta fusion protein, human; D014443:Tyrosine; D010649:Phenylalanine