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

Oncogene. 2004 Jun 10;23(27):4690-706. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Down-Regulation
  • ErbB Receptors / antagonists & inhibitors
  • 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 / metabolism
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / isolation & purification
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-cbl
  • RNA, Small Interfering / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Subcellular Fractions / metabolism
  • Sulfhydryl Compounds / chemistry
  • T-Lymphocytes / metabolism*
  • Tissue Distribution
  • Transcription Factors / metabolism
  • U937 Cells
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / chemistry*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / isolation & purification
  • Ubiquitin-Protein Ligases / metabolism*


  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell
  • Sulfhydryl Compounds
  • Transcription Factors
  • Ubiquitin
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • CBL protein, human