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.
Sattler
Martin
M
Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA. martin_sattler@dfci.harvard.edu
Pride
Yuri B
YB
Quinnan
Laura R
LR
Verma
Shalini
S
Malouf
Nicole A
NA
Husson
Hervé
H
Salgia
Ravi
R
Lipkowitz
Stanley
S
Griffin
James D
JD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D050722:Oncogene Protein v-cbl; D015513:Oncogene Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl; D051573:Proto-Oncogene Proteins c-pim-1; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D016044:Fusion Proteins, bcr-abl; D006861:Hydrogen Peroxide; D009687:Nuclear Proteins; D050722:Oncogene Protein v-cbl; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D051573:Proto-Oncogene Proteins c-pim-1; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger; D015682:Retroviridae Proteins, Oncogenic; D044767:Ubiquitin-Protein Ligases; C082869:CRKL protein; C118387:Cblb protein, mouse; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; C492211:CBLB protein, human; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse