The online version of this article (doi:10.1186/1476-4598-11-6) contains supplementary material, which is available to authorized users.
Maria Meehan, Laavanya Parthasarathi contributed equally to this work.
The authors declare that they have no competing interests.
MM, LP, EL, NF, JR conceived and performed experiments and assisted with writing the manuscript. CAJ, NM, DM and RLS conceived experiments and assisted with writing the manuscript. BO, AF and TAC provided unique research materials. All authors read and approved the final manuscript
Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. 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.
As a 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 in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma.
PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.
Additional File 1: Expression of PTPRD (A) mRNA and (B) protein following transfection of Kelly cells with increasing concentrations of PTPRD cDNA. mRNA was extracted at 24 hours and qPCR was performed. Lysates were harvested at 48 h and subjected to SDS PAGE and western blot analysis with a monoclonal antibody to the V5 epitope tag or alpha tubulin. All experiments were performed in triplicate. (TIFF 92 KB)12943_2011_985_MOESM1_ESM.TIFF
Additional File 2: (A) Expression of AURKA mRNA 48 hours post PTPRD expression. Either 1 μg of PTPRD or empty vector (E.V.) were transfected into Kelly cells. mRNA was extracted at 48 hours and qPCR was performed. The figure is representative of four independent experiments and E.V. is set as 1.0. (B) Expression of MYCN mRNA 48 hours post PTPRD expression. Either 1 μg of PTPRD or empty vector (E.V.) were transfected into Kelly cells. mRNA was extracted at 48 hours and qPCR was performed. The figure is representative of four independent experiments and E.V. is set as 1.0. (TIFF 101 KB)12943_2011_985_MOESM2_ESM.TIFF
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- Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene
Caroline A Jefferies
Armida W M Fabius
Timothy A Chan
Raymond L Stallings
- BioMed Central
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