Crkl is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia.

The deregulated tyrosine kinase activity of the Bcr/Abl protein has been causally linked to the development of Philadelphia (Ph) chromosome-positive leukemia in mice and man. Abnormally tyrosine-phosphorylated substrates of the Bcr/Abl kinase in Ph-positive cells are likely to contribute to leukemogenesis by interfering with normal signal transduction pathways. We have ...
previously shown that the adaptor molecule Crkl is a major in vivo substrate for the Bcr/Abl tyrosine kinase, and it is thought to connect Bcr/Abl with downstream effectors. In the current study, a tyrosine-phosphorylated protein with a molecular mass of approximately 120 kDa was identified which binds only to the Crkl Src homology 2 (SH2) domain in cells, including Ph-positive patient material, containing an active Bcr/Abl protein. We demonstrate here that this protein is Cbl, originally discovered as an oncogene which induces B-cell and myeloid leukemias in mice. The Crkl SH2 domain binds specifically to Cbl. The Src homology 3 (SH3) domains of Crkl do not bind to Cbl, but do bind Bcr/Abl. These findings suggest the existence of a trimolecular complex involving Bcr/Abl, Crkl, and Cbl and are consistent with a model in which Crkl mediates the oncogenic signal of Bcr/Abl to Cbl.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Binding Sites, Cell Line, Electrophoresis, Polyacrylamide Gel, Fusion Proteins, bcr-abl, Glutathione Transferase, Humans, Leukemia, Erythroblastic, Acute, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Molecular Weight, Nuclear Proteins, Oncogene Protein v-cbl, Phosphorylation, Phosphotyrosine, Recombinant Fusion Proteins, Retroviridae Proteins, Oncogenic, Tumor Cells, Cultured, Tyrosine
J. Biol. Chem.
Date: Sep. 15, 1995
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