TULA: an SH3- and UBA-containing protein that binds to c-Cbl and ubiquitin

• Published in: Oncogene Vol. 23; no. 27; pp. 4690 - 4706
• Main Authors: FESHCHENKO, Elena A, SMIRNOVA, Evgeniya V, SWAMINATHAN, Gayathri, TECKCHANDANI, Anjali M, AGRAWAL, Rachana, BAND, Hamid, XIAOLONG ZHANG, ANNAN, Roland S, CARR, Steven A, TSYGANKOV, Alexander Y
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 10-06-2004; Nature Publishing Group
• Subjects: Affinity chromatography; Amino Acid Substitution; Animals; Base Sequence; Biological and medical sciences; Cbl protein; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cercopithecus aethiops; COS Cells; Down-Regulation; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; HeLa Cells; HL-60 Cells; Humans; Immunology; Jurkat Cells; Kinases; Ligands; Lymphocytes T; Mass spectroscopy; Molecular and cellular biology; Molecular Sequence Data; Mutagenesis, Site-Directed; NF-AT protein; Protein Binding; Protein C; Protein Structure, Tertiary; Protein-Tyrosine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - isolation & purification; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-cbl; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptors, Antigen, T-Cell - metabolism; RNA, Small Interfering - metabolism; Subcellular Fractions - metabolism; Sulfhydryl Compounds - chemistry; T-Lymphocytes - metabolism; Tissue Distribution; Transcription Factors - metabolism; Tyrosine; U937 Cells; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - isolation & purification; Ubiquitin-Protein Ligases - metabolism; United States > US; Ubiquitin; TULA; Enzyme; UBA; protein tyrosine kinase; Transferases; c-Cbl; Carcinogenesis; Protein-tyrosine kinase; Protein; SH3
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207627

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.