title: Mutational and functional analysis of the tumor-suppressor PTPRD in human melanoma.
abstract: 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 (PTPRD) was one of the most highly mutated genes, harboring 17 somatic mutations in 79 samples, a prevalence of 21.5%. Functional evaluation of six PTPRD mutations revealed enhanced anchorage-dependent and anchorage-independent growth. Interestingly, melanoma cells expressing mutant PTPRD were significantly more migratory than cells expressing wild-type PTPRD 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 PTPRD is also mutated in glioblastomas and adenocarcinoma of the colon and lung, our data might be applicable to a large number of human cancers.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Vijay
authors.initials: V
authors.lastname: Walia
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.forename: Jung-Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Gartner
authors.forename: Jimmy C
authors.initials: JC
authors.lastname: Lin
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Randolph C
authors.initials: RC
authors.lastname: Elble
authors.forename: David A
authors.initials: DA
authors.lastname: Solomon
authors.forename: Todd
authors.initials: T
authors.lastname: Waldman
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
mesh_terms: D002352:Carrier Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D051180:Desmoplakins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D002352:Carrier Proteins; D051180:Desmoplakins; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: PTPRD; cell migration; desmoplakin; desmosomes; somatic mutations
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