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Mutational analysis of the tyrosine phosphatome in colorectal cancers
Zhenghe Wang1, Dong Shen, D Williams Parsons
1Sidney Kimmel Comprehensive Cancer Center, Howard Hughes Medical Institute, Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA.
Abstract:
Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs (PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Fifteen mutations were nonsense, frameshift, or splice-site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP (PTPRT) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the mutated tyrosine phosphatases are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.
Insights
Mutations in tyrosine phosphatase genes are common in cancers, particularly colorectal cancer. These altered phosphatases act as tumor suppressors, suggesting new therapeutic targets for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tyrosine phosphorylation is crucial in cancer signaling pathways.
- Protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) regulate this process.
- Dysregulation of PTPs is implicated in tumorigenesis.
Purpose of the Study:
- To investigate the role of PTPs in human cancers through mutational analysis.
- To identify specific PTP genes frequently mutated in various cancer types.
- To assess the functional impact of identified mutations on PTP activity and cellular growth.
Main Methods:
- Somatic mutation analysis of the tyrosine phosphatase gene superfamily in human cancer datasets.
- Identification and classification of mutations (nonsense, frameshift, splice-site, missense).
- Biochemical assays to determine the phosphatase activity of mutated PTPs, specifically PTPRT.
- Cell-based assays to evaluate the effect of wild-type and mutant PTPRT expression on cancer cell growth.
Main Results:
- Identified 83 somatic mutations in six PTPs across human cancers.
- Found mutations in 26% of colorectal cancers and a smaller proportion of lung, breast, and gastric cancers.
- Fifteen mutations predicted to abolish phosphatase activity.
- Five missense mutations in PTPRT demonstrated reduced phosphatase activity.
- Wild-type PTPRT expression inhibited cancer cell growth, while mutant PTPRT did not.
Conclusions:
- Mutated tyrosine phosphatases function as tumor suppressor genes.
- These PTPs regulate critical cellular pathways involved in cancer development.
- The findings suggest potential therapeutic strategies targeting these pathways for cancer intervention.
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