Mutational analysis of the tyrosine phosphatome in colorectal cancers.
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.
Wang
Zhenghe
Z
Sidney Kimmel Comprehensive Cancer Center, Howard Hughes Medical Institute, Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA.
Shen
Dong
D
Parsons
D Williams
DW
Bardelli
Alberto
A
Sager
Jason
J
Szabo
Steve
S
Ptak
Janine
J
Silliman
Natalie
N
Peters
Brock A
BA
van der Heijden
Michiel S
MS
Parmigiani
Giovanni
G
Yan
Hai
H
Wang
Tian-Li
TL
Riggins
Greg
G
Powell
Steven M
SM
Willson
James K V
JK
Markowitz
Sanford
S
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
Velculescu
Victor E
VE
D020134:Catalytic Domain; D002455:Cell Division; D018389:Codon, Nonsense; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics*; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005091:Exons; D016368:Frameshift Mutation; D016147:Genes, Tumor Suppressor; D006801:Humans; D007700:Kinetics; D008390:Markov Chains; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*
D018389:Codon, Nonsense; D009419:Nerve Tissue Proteins; D014443:Tyrosine; C516742:PTPN13 protein, human; C516656:PTPN3 protein, human; C516850:PTPRG protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3; D017027:Protein Tyrosine Phosphatases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5