Mutational Analysis of the Tyrosine Phosphatome in Colorectal Cancers
Zhenghe Wang,1
Dong Shen,1*
D. Williams Parsons,1*
Alberto Bardelli,1*
Jason Sager,1
Steve Szabo,1
Janine Ptak,1
Natalie Silliman,1
Brock A. Peters,1
Michiel S. van der Heijden,1
Giovanni Parmigiani,1
Hai Yan,2
Tian-Li Wang,1
Greg Riggins,1
Steven M. Powell,3
James K. V. Willson,4
Sanford Markowitz,4
Kenneth W. Kinzler,1
Bert Vogelstein,1
Victor E. Velculescu1
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.
1 The Sidney Kimmel Comprehensive Cancer Center, The Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA.
2 Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
3 Division of Gastroenterology/Heptalogy, UVA Health System, Charlottesville, VA 22908, USA.
4 Howard Hughes Medical Institute and Department of Medicine and Ireland Cancer Center, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106, USA
* These authors contributed equally to this work.
To whom correspondence should be addressed: E-mail: velculescu{at}jhmi.edu
