Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells.
CBL and the related CBL-B protein are two members of a family of RING finger type ubiquitin E3 ligases that are believed to function as negative regulators of signal transduction in hematopoietic and immune cells. In mice, expression of v-Cbl causes lymphomas, and targeted disruption of either the CBL gene ... or the CBL-B gene can result in a lymphoproliferative disorder or hypersensitivity of lymphocytes. CBL is one of the most prominent targets of the BCR/ABL tyrosine kinase oncogene. We compared the role of CBL and CBL-B in signal transduction of BCR/ABL using pairs of cell lines before and after expression of BCR/ABL. In contrast to CBL, BCR/ABL was found to rapidly downregulate the expression of CBL-B protein. The decrease in CBL-B protein induced by BCR/ABL was associated with downregulation of CBL-B mRNA. Downregulation and tyrosine phosphorylation of CBL-B required BCR/ABL kinase activity. However, despite their known similarities in structure and function, we found CBL and CBL-B proteins to be involved in distinct signaling complexes. CBL was predominantly in a complex with phosphatidylinositol 3'-kinase and CRKL, while CBL-B was not associated with any significant phosphatidylinositol 3'-kinase activity. A major CBL-B associated protein was identified as mono-ubiquitinated Vav, a nucleotide exchange factor for Rac1. These results demonstrate that BCR/ABL signals differentially through CBL and CBL-B, with downregulation of the CBL-B protein potentially contributing to BCR/ABL-mediated transformation.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Line, Transformed, Cell Movement, Cell Transformation, Neoplastic, Down-Regulation, Fusion Proteins, bcr-abl, Gene Expression Regulation, Neoplastic, Genes, abl, Humans, Hydrogen Peroxide, Mice, Nuclear Proteins, Oncogene Protein v-cbl, Oncogene Proteins, Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-pim-1, Proto-Oncogene Proteins c-vav, RNA, Messenger, Retroviridae Proteins, Oncogenic, Signal Transduction, Transfection, Ubiquitin-Protein Ligases
1-Phosphatidylinositol 3-Kinase, Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Line, Transformed, Cell Movement, Cell Transformation, Neoplastic, Down-Regulation, Fusion Proteins, bcr-abl, Gene Expression Regulation, Neoplastic, Genes, abl, Humans, Hydrogen Peroxide, Mice, Nuclear Proteins, Oncogene Protein v-cbl, Oncogene Proteins, Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-pim-1, Proto-Oncogene Proteins c-vav, RNA, Messenger, Retroviridae Proteins, Oncogenic, Signal Transduction, Transfection, Ubiquitin-Protein Ligases
Oncogene
Date: Feb. 21, 2002
PubMed ID: 11857085
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