PUBLICATION

c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/β-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation

Authors
Kumaradevan, S., Lee, S.Y., Richards, S., Lyle, C., Zhao, Q., Tapan, U., Jiangliu, Y., Ghumman, S., Walker, J., Belghasem, M., Arinze, N., Kuhnen, A., Weinberg, J., Francis, J., Hartshorn, K., Kolachalama, V.B., Cifuentes, D., Rahimi, N., Chitalia, V.C.
ID
ZDB-PUB-180722-15
Date
2018
Source
The American journal of pathology   188(8): 1921-1933 (Journal)
Registered Authors
Cifuentes, Daniel
Keywords
none
MeSH Terms
  • Phosphorylation
  • Wnt1 Protein/genetics
  • Wnt1 Protein/metabolism*
  • Prognosis
  • Biomarkers, Tumor/genetics
  • Biomarkers, Tumor/metabolism*
  • Case-Control Studies
  • beta Catenin/genetics
  • beta Catenin/metabolism*
  • Male
  • Tumor Cells, Cultured
  • Follow-Up Studies
  • Colorectal Neoplasms/genetics
  • Colorectal Neoplasms/metabolism
  • Colorectal Neoplasms/mortality*
  • Colorectal Neoplasms/pathology
  • Tyrosine/metabolism*
  • Proto-Oncogene Proteins c-cbl/genetics
  • Proto-Oncogene Proteins c-cbl/metabolism*
  • Female
  • Cell Proliferation
  • Animals
  • Middle Aged
  • Zebrafish
  • Survival Rate
  • Apoptosis
  • Mutation
  • Humans
  • Neovascularization, Pathologic
(all 29)
PubMed
30029779 Full text @ Am. J. Pathol.
Abstract
The proto-oncogene β-catenin drives colorectal cancer (CRC) tumorigenesis. Casitas B-lineage lymphoma (c-Cbl) inhibits CRC tumor growth through targeting nuclear β-catenin by a poorly understood mechanism. In addition, the role of c-Cbl in human CRC remains largely underexplored. Using a novel quantitative histopathologic technique, we demonstrate that patients with high c-Cbl-expressing tumors had significantly better median survival (3.7 years) compared with low c-Cbl-expressing tumors (1.8 years; P = 0.0026) and were more than twice as likely to be alive at 3 years compared with low c-Cbl tumors (P = 0.0171). Our data further demonstrate that c-Cbl regulation of nuclear β-catenin requires phosphorylation of c-Cbl Tyr371 because its mutation compromises its ability to target β-catenin. The tyrosine 371 (Y371H) mutant interacted with but failed to ubiquitinate nuclear β-catenin. The nuclear localization of the c-Cbl-Y371H mutant contributed to its dominant negative effect on nuclear β-catenin. The biological importance of c-Cbl-Y371H was demonstrated in various systems, including a transgenic Wnt-8 zebrafish model. c-Cbl-Y371H mutant showed augmented Wnt/β-catenin signaling, increased Wnt target genes, angiogenesis, and CRC tumor growth. This study demonstrates a strong link between c-Cbl and overall survival of patients with CRC and provides new insights into a possible role of Tyr371 phosphorylation in Wnt/β-catenin regulation, which has important implications in tumor growth and angiogenesis in CRC.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Kumaradevan, S., Lee, S.Y., Richards, S., Lyle, C., Zhao, Q., Tapan, U., Jiangliu, Y., Ghumman, S., Walker, J., Belghasem, M., Arinze, N., Kuhnen, A., Weinberg, J., Francis, J., Hartshorn, K., Kolachalama, V.B., Cifuentes, D., Rahimi, N., Chitalia, V.C. (2018) c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/β-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation. The American journal of pathology. 188(8):1921-1933.