Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Transformed
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Cell Movement
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Down-Regulation
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, abl / genetics
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Humans
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Hydrogen Peroxide / pharmacology
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Mice
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Nuclear Proteins / metabolism
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Oncogene Protein v-cbl
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Oncogene Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation
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Phosphotyrosine / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-cbl
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Proto-Oncogene Proteins c-pim-1
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Proto-Oncogene Proteins c-vav
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Retroviridae Proteins, Oncogenic / genetics
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Retroviridae Proteins, Oncogenic / metabolism*
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Signal Transduction* / drug effects
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Transfection
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Ubiquitin-Protein Ligases*
Substances
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Adaptor Proteins, Signal Transducing
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CRKL protein
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Carrier Proteins
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Cblb protein, mouse
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Nuclear Proteins
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Oncogene Protein v-cbl
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Oncogene Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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RNA, Messenger
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Retroviridae Proteins, Oncogenic
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VAV1 protein, human
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Vav1 protein, mouse
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Phosphotyrosine
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Hydrogen Peroxide
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Fusion Proteins, bcr-abl
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PIM1 protein, human
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Pim1 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-pim-1