Abstract
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.
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Abbreviations
- LZ:
-
leucine zipper
- PTK:
-
protein tyrosine kinase
- siRNA:
-
short interfering RNA
- RNAi:
-
RNA interference
- TKB:
-
tyrosine kinase-binding domain
- TCR:
-
T-cell receptor for antigen
- UBA:
-
ubiquitylation-associated domain
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Acknowledgements
We thank Drs D Bohmann, W Langdon, S Lipkowitz, M Monestier, L Samelson, and Y Yarden for their kind gift of reagents, Dr M Chan for her generous help with real-time PCR, and G Harvey for his excellent editorial help. This work was supported by NIH grant CA78499 to AYT.
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Feshchenko, E., Smirnova, E., Swaminathan, G. et al. TULA: an SH3- and UBA-containing protein that binds to c-Cbl and ubiquitin. Oncogene 23, 4690–4706 (2004). https://doi.org/10.1038/sj.onc.1207627
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DOI: https://doi.org/10.1038/sj.onc.1207627
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