title: The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers.
abstract: Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Selvaraju
authors.initials: S
authors.lastname: Veeriah
authors.forename: Cameron
authors.initials: C
authors.lastname: Brennan
authors.forename: Shasha
authors.initials: S
authors.lastname: Meng
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.forename: Dan
authors.initials: D
authors.lastname: Rohle
authors.forename: Igor
authors.initials: I
authors.lastname: Vivanco
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: William L
authors.initials: WL
authors.lastname: Gerald
authors.forename: Linda
authors.initials: L
authors.lastname: Liau
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cloughesy
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Barry
authors.initials: B
authors.lastname: Taylor
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: John
authors.initials: J
authors.lastname: Major
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
mesh_terms: D019175:DNA Methylation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2