Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase A oncogene.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Dublin, Ireland.
Maria
M
Meehan
Laavanya
L
Parthasarathi
Niamh
N
Moran
Caroline A
CA
Jefferies
Niamh
N
Foley
Elisa
E
Lazzari
Derek
D
Murphy
Jacqueline
J
Ryan
Berenice
B
Ortiz
Armida W M
AW
Fabius
Timothy A
TA
Chan
Raymond L
RL
Stallings
D017209:Apoptosis / Q000235:genetics; D064096:Aurora Kinase A; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D004795:Enzyme Stability; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D015513:Oncogene Proteins; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2