The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers.
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.
Veeriah
Selvaraju
S
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Brennan
Cameron
C
Meng
Shasha
S
Singh
Bhuvanesh
B
Fagin
James A
JA
Solit
David B
DB
Paty
Philip B
PB
Rohle
Dan
D
Vivanco
Igor
I
Chmielecki
Juliann
J
Pao
William
W
Ladanyi
Marc
M
Gerald
William L
WL
Liau
Linda
L
Cloughesy
Timothy C
TC
Mischel
Paul S
PS
Sander
Chris
C
Taylor
Barry
B
Schultz
Nikolaus
N
Major
John
J
Heguy
Adriana
A
Fang
Fang
F
Mellinghoff
Ingo K
IK
Chan
Timothy A
TA
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
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2