A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase.
A direct binding site for the Grb2 adapter protein is required for the induction of fatal chronic myeloid leukemia (CML)-like disease in mice by Bcr-Abl. Here, we demonstrate direct binding of Grb2 to the Tel-Abl (ETV6-Abl) fusion protein, the product of complex (9;12) chromosomal translocations in human leukemia, via tyrosine 314 encoded by TEL exon 5. A Tel-Abl point mutant (Y314F) and a splice variant without TEL exon 5 sequences (Deltae5) lacked Grb2 interaction and exhibited decreased binding and phosphorylation of the scaffolding protein Gab2 and impaired activation of phosphatidylinositol 3-kinase, Akt, and extracellular signal-regulated kinase/mitogen-activated protein kinase in hematopoietic cells. Tel-Abl Y314F and Deltae5 were unable to transform fibroblasts to anchorage-independent growth and were defective for B-lymphoid transformation in vitro and lymphoid leukemogenesis in vivo. Previously, we demonstrated that full-length Tel-Abl induced two distinct myeloproliferative diseases in mice: CML-like leukemia similar to that induced by Bcr-Abl and a novel syndrome of small-bowel myeloid infiltration endotoxemia and hepatic and renal failure. Lack of the Grb2 binding site had no effect on development of small bowel syndrome but significantly attenuated the induction of CML-like disease by Tel-Abl. These results suggest that direct binding of Grb2 is a common mechanism contributing to leukemogenesis by oncogenic Abl fusion proteins.
Million
Ryan P
RP
Molecular Oncology Research Institute, Tufts-New England Medical Center, 750 Washington St., Box 5609, Boston, MA 02111, USA.
Harakawa
Nari
N
Roumiantsev
Sergei
S
Varticovski
Lyuba
L
Van Etten
Richard A
RA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D007938:Leukemia / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D020928:Mitogen-Activated Protein Kinases; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D014443:Tyrosine; C495949:Grb2 protein, mouse; C426234:TEL-ABL fusion protein, human; D000097764:ETS Translocation Variant 6 Protein