Mutational Analysis of the Tyrosine Phosphatome in Colorectal Cancers

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.

Copy number variants in patients with short stature

“…Both genes are considered tumor suppressors. 34,35 The 6q duplication that case II.7 inherited from his mother is located nearby (97 kb downstream) a locus (TULP4) associated with height. 1 One of the duplicated genes (ENPP2) in case II.8 encodes for a lysophospholipase D, producing lysophosphatidic acid inducing cell proliferation.…”

Normal TCR Signal Transduction in Mice That Lack Catalytically Active PTPN3 Protein Tyrosine Phosphatase

“…Finally, in a recent study, PTPN3 was identified as 1 of 6 PTPs of all 87 that are encoded in the human genome to be frequently mutated in colorectal cancer cell lines (36). Interestingly, of the other 5 PTPs, 1, PTPL1/FAP-1 (PTPN13), also contains FERM and PDZ domains and another, PTP36/PEZ (PTPN14), contains a FERM domain.…”

Identifying Molecular Markers for the Early Detection of Pancreatic Neoplasia

“…For example, kinome sequencing has involved sequencing the coding regions of several hundred kinase genes, such as the tyrosine kinases. This approach has led to the discovery of mutations in several kinase genes including tyrosine kinase, tyrosine phosphatase and lipid kinase genes in colorectal cancer [109][110][111][112] . Similarly, sequencing known components of an important signaling pathway led to the identification of BRAF mutations in melanomas 113 .…”