Mutational and Functional Analysis of the Tumor‐Suppressor PTPRD in Human Melanoma. Issue 11 (10th September 2014)

• Record Type: Journal Article
• Authors: Walia, Vijay; Prickett, Todd D.; Kim, Jung‐Sik; Gartner, Jared J.; Lin, Jimmy C.; Zhou, Ming; Rosenberg, Steven A.; Elble, Randolph C.; Solomon, David A.; Waldman, Todd; Samuels, Yardena
• Is Part Of: Human mutation. Volume 35:Issue 11(2014:Nov.)
• Page Start: 1301
• Page End: 1310
• Publication Date: 2014-09-10
• Subjects: Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22630
• Languages: English
• ISSNs: 1059-7794

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Protein tyrosine phosphatases (PTPs) tightly regulate tyrosine phosphorylation essential for cell growth, adhesion, migration, and survival. We performed a mutational analysis of the PTP gene family in cutaneous metastatic melanoma and identified 23 phosphatase genes harboring somatic mutations. Among these, receptor‐type tyrosine–protein phosphatase delta (<italic>PTPRD</italic>) was one of the most highly mutated genes, harboring 17 somatic mutations in 79 samples, a prevalence of 21.5%. Functional evaluation of six <italic>PTPRD</italic> mutations revealed enhanced anchorage‐dependent and anchorage‐independent growth. Interestingly, melanoma cells expressing mutant <italic>PTPRD</italic> were significantly more migratory than cells expressing wild‐type <italic>PTPRD</italic> or vector alone, indicating a novel gain‐of‐function associated with mutant PTPRD. To understand the molecular mechanisms of PTPRD mutations, we searched for its binding partners by converting the active PTPRD enzyme into a "substrate trap" form. Using mass spectrometry and coimmunoprecipitation, we report desmoplakin, a desmosomal protein that is implicated in cell–cell adhesion, as a novel PTPRD substrate. Further analysis showed reduced phosphatase activity of mutant PTPRD against desmoplakin. Our findings identify an essential signaling cascade that is disrupted in melanoma. Moreover, because <italic>PTPRD</italic> is also mutated in glioblastomas and adenocarcinoma of the colon and lung, our data might be applicable to a large number of human cancers.</p> </abstract>