TY - JOUR
T1 - TULA
T2 - An SH3- And UBA-containing protein that binds to c-Cbl and ubiquitin
AU - Feshchenko, Elena A.
AU - Smirnova, Evgeniya V.
AU - Swaminathan, Gayathri
AU - Teckchandani, Anjali M.
AU - Agrawal, Rachana
AU - Band, Hamid
AU - Zhang, Xiaolong
AU - Annan, Roland S.
AU - Carr, Steven A.
AU - Tsygankov, Alexander Y.
N1 - Funding Information:
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.
PY - 2004/6/10
Y1 - 2004/6/10
N2 - Bownregulation 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.
AB - Bownregulation 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.
KW - Protein tyrosine kinase
KW - SH3
KW - TULA
KW - UBA
KW - Ubiquitin
KW - c-Cbl
UR - http://www.scopus.com/inward/record.url?scp=2942720847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2942720847&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1207627
DO - 10.1038/sj.onc.1207627
M3 - Article
C2 - 15107835
AN - SCOPUS:2942720847
VL - 23
SP - 4690
EP - 4706
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 27
ER -