5789

PTPRD

HPTP|HPTPD|HPTPDELTA|PTPD|RPTPDELTA;protein tyrosine phosphatase, receptor type, D;PTPRD;protein tyrosine phosphatase, receptor type, D

R-PTP-delta|protein tyrosine phosphatase, receptor type, delta polypeptide|protein-tyrosine phosphatase delta|receptor-type tyrosine-protein phosphatase delta

9p23-p24.3

protein-coding

Neuroblastoma (NBL), a pediatric tumor arising from precursor cells of the sympathetic nervous system, is characterized by numerous recurrent large-scale chromosomal imbalances. High resolution oligonucleotide array CGH analysis of NBL has previously identified microdeletions that are confined to the 5' UTR of the protein tyrosine phosphatase receptor D (PTPRD) gene, implicating this gene in the pathogenesis of these tumors. Here, we demonstrate that the 5' UTR of this gene, consisting of 11 noncoding exons, is also aberrantly spliced in >50% of NBL primary tumors and cell lines. The loss of exons from the 5' UTR region through aberrant splicing results in aberrant mRNA isoforms that are similar to those generated through microdeletions. The aberrant splicing or microdeletion of 5' UTR exons in such a high proportion of tumors indicates that loss of these exonsdys-regulates the mRNA sequence. To further validate the role of PTPRD in NBL, we have examined the expression of this gene in normal fetal adrenal neuroblasts (the cell of origin of NBL) and in tumors from patients with either low stage orhigh stage disease. This gene is expressed at lower levels in high stage NBL tumors, particularly those with amplification of MYCN, relative to low stage tumors or normal fetal adrenal neuroblasts, consistent with the possibility thatloss of the 5' UTR exons have destabilized the mRNA.#CI- (c) 2007 Wiley-Liss, Inc.

BACKGROUND: Protein tyrosine phosphatase receptor delta (PTPRD) is a member of alarge family of protein tyrosine phosphatases which negatively regulate tyrosinephosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. RESULTS: Asa molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA's primary functions inneuroblastoma, the stabilization of MYCN protein, the gene of which is amplifiedin approximately 25 to 30% of high risk neuroblastoma. CONCLUSIONS: PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing anovel mechanism for the function of PTPRD in neuroblastoma.