title: Tumor derived mutations of protein tyrosine phosphatase receptor type k affect its function and alter sensitivity to chemotherapeutics in glioma.
abstract: Poor prognosis and resistance to therapy in malignant gliomas is mainly due to the highly dispersive nature of glioma cells. This dispersive characteristic results from genetic alterations in key regulators of cell migration and diffusion. A better understanding of these regulatory signals holds promise to improve overall survival and response to therapy. Using mapping arrays to screen for genomic alterations in gliomas, we recently identified alterations of the protein tyrosine phosphatase receptor type kappa gene (PTPRK) that correlate to patient outcomes. These PTPRK alterations are very relevant to glioma biology as PTPRK can directly sense cell-cell contact and is a dephosphorylation regulator of tyrosine phosphorylation signaling, which is a major driving force behind tumor development and progression. Subsequent sequencing of the full length PTPRK transcripts revealed novel PTPRK gene deletion and missense mutations in numerous glioma biopsies. PTPRK mutations were cloned and expressed in PTPRK-null malignant glioma cells. The effect of these mutations on PTPRK anti-oncogenic function and their association with response to anti-glioma therapeutics, such as temozolomide and tyrosine kinase inhibitors, was subsequently analyzed using in vitro cell-based assays. These genetic variations altered PTPRK activity and its post-translational processing. Reconstitution of wild-type PTPRK in malignant glioma cell lines suppressed cell growth and migration by inhibiting EGFR and β-catenin signaling and improved the effect of conventional therapies for glioma. However, PTPRK mutations abrogated tumor suppressive effects of wild-type PTPRK and altered sensitivity of glioma cells to chemotherapy.
authors.affiliation: Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Supreet
authors.initials: S
authors.lastname: Agarwal
authors.forename: Maha S
authors.initials: MS
authors.lastname: Al-Keilani
authors.forename: Mohammad A Y
authors.initials: MA
authors.lastname: Alqudah
authors.forename: Zita A
authors.initials: ZA
authors.lastname: Sibenaller
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Ryken
authors.forename: Mahfoud
authors.initials: M
authors.lastname: Assem
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D009154:Mutation; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D003606:Dacarbazine; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D000077204:Temozolomide