The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways.
Inappropriate activation of Abl family kinases plays a crucial role in different human leukaemias. In addition to the well known oncoproteins p190Bcr-Abl and p210Bcr-Abl, Tel-Abl, a novel fusion protein resulting from a different chromosomal translocation, has recently been described. In this study, the kinase specificities of the Bcr-Abl and Tel-Abl proteins were compared to the physiological Abl family kinases c-Abl and Arg (abl related gene). Using short peptides which correspond to the target epitopes in known substrate proteins of Abl family kinases, we found a higher catalytic promiscuity of Bcr-Abl and Tel-Abl. Similar to Bcr-Abl, Tel-Abl was found in complexes with the adapter protein CRKL. In addition, c-Crk II and CRKL are tyrosine phosphorylated and complexed with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3 cells. GTPase analysis with a Ras-GTP-specific precipitation assay showed constitutive elevation of GTP-loaded Ras in cells expressing the leukaemic Abl proteins. The mitogenic MAPK/Erk kinases as well as Akt/PKB, a kinase implicated to negatively regulate apoptosis, were also constitutively activated by both Bcr-Abl and Tel-Abl. The results indicate that the leukaemic Abl-fusion proteins have catalytic specificities different from the normal kinases c-Abl and Arg and that Tel-Abl is capable to activate at least some pathways which are also upregulated by Bcr-Abl.
Voss
J
J
Laboratory of Molecular Oncology, Institut für Medizinische Strahlenkunde und Zellforschung, Würzburg, Germany.
Posern
G
G
Hannemann
J R
JR
Wiedemann
L M
LM
Turhan
A G
AG
Poirel
H
H
Bernard
O A
OA
Adermann
K
K
Kardinal
C
C
Feller
S M
SM
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D002460:Cell Line; D000939:Epitopes / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000502:physiology; D006412:Hematopoietic Stem Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050737:Proto-Oncogene Proteins c-crk; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D013379:Substrate Specificity; D014178:Translocation, Genetic
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D000939:Epitopes; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D006160:Guanosine Triphosphate; D016315:Proto-Oncogene Proteins c-abl; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)