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

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An Erratum to this article was published on 16 December 2004

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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Author notes

  1. Elena A Feshchenko

    Present address: Curagen, Branford, CT, USA

  2. Hamid Band

    Present address: Feinberg School of Medicine, Northwestern University, Evanston, IL, USA

  3. Xiaolong Zhang

    Present address: Celera Genomics, Rockville, MD, USA

  4. Steven A Carr

    Present address: Millennium Pharmaceuticals, Cambridge, MA, USA

Authors and Affiliations

  1. Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA

    Elena A Feshchenko, Evgeniya V Smirnova, Gayathri Swaminathan, Anjali M Teckchandani, Rachana Agrawal & Alexander Y Tsygankov

  2. GlaxoSmithKline, King of Prussia, PA, USA

    Hamid Band

  3. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    Xiaolong Zhang, Roland S Annan & Steven A Carr

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  1. Elena A Feshchenko
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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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