TULA: an SH3- and UBA-containing protein that binds to c-Cbl and ubiquitin.
Downregulation of protein tyrosine kinases is a major function of the multidomain protein c-Cbl. This effect of c-Cbl is critical for both negative regulation of normal physiological stimuli and suppression of cellular transformation. In spite of the apparent importance of these effects of c-Cbl, their own regulation is poorly understood. ... To search for possible novel regulators of c-Cbl, we purified a number of c-Cbl-associated proteins by affinity chromatography and identified them by mass spectrometry. Among them, we identified the UBA- and SH3-containing protein T-cell Ubiquitin LigAnd (TULA), which can also bind to ubiquitin. Functional studies in a model system based on co-expression of TULA, c-Cbl, and EGF receptor in 293T cells demonstrate that TULA is capable of inhibiting c-Cbl-mediated downregulation of EGF receptor. Furthermore, modulation of TULA concentration in Jurkat T-lymphoblastoid cells demonstrates that TULA upregulates the activity of both Zap kinase and NF-AT transcription factor. Therefore, our study indicates that TULA counters the inhibitory effect of c-Cbl on protein tyrosine kinases and, thus, may be involved in the regulation of biological effects of c-Cbl. Finally, our results suggest that TULA-mediated inhibition of the effects of c-Cbl on protein tyrosine kinases is caused by TULA-induced ubiquitylation and degradation of c-Cbl.
Mesh Terms:
Amino Acid Substitution, Animals, Base Sequence, COS Cells, Cell Line, Tumor, Cercopithecus aethiops, Down-Regulation, Gene Expression Regulation, Neoplastic, HL-60 Cells, Hela Cells, Humans, Jurkat Cells, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Binding, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, RNA, Small Interfering, Receptor, Epidermal Growth Factor, Receptors, Antigen, T-Cell, Subcellular Fractions, Sulfhydryl Compounds, T-Lymphocytes, Tissue Distribution, Transcription Factors, U937 Cells, Ubiquitin, Ubiquitin-Protein Ligases
Amino Acid Substitution, Animals, Base Sequence, COS Cells, Cell Line, Tumor, Cercopithecus aethiops, Down-Regulation, Gene Expression Regulation, Neoplastic, HL-60 Cells, Hela Cells, Humans, Jurkat Cells, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Binding, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, RNA, Small Interfering, Receptor, Epidermal Growth Factor, Receptors, Antigen, T-Cell, Subcellular Fractions, Sulfhydryl Compounds, T-Lymphocytes, Tissue Distribution, Transcription Factors, U937 Cells, Ubiquitin, Ubiquitin-Protein Ligases
Oncogene
Date: Jun. 10, 2004
PubMed ID: 15107835
View in: Pubmed Google Scholar
Download Curated Data For This Publication
109190
Switch View:
- Interactions 11
- PTM Genes 1