Mutational analysis of the tyrosine phosphatome in colorectal cancers |
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| Authors: | Wang Zhenghe Shen Dong Parsons D Williams Bardelli Alberto Sager Jason Szabo Steve Ptak Janine Silliman Natalie Peters Brock A van der Heijden Michiel S Parmigiani Giovanni Yan Hai Wang Tian-Li Riggins Greg Powell Steven M Willson James K V Markowitz Sanford Kinzler Kenneth W Vogelstein Bert Velculescu Victor E |
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| Institution: | Sidney Kimmel Comprehensive Cancer Center, Howard Hughes Medical Institute, Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA. |
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| 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. |
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