Document Type

Article

Peer Reviewed

1

Publication Date

5-16-2013

NLM Title Abbreviation

PLoS One

Journal/Book/Conference Title

PLoS ONE

PubMed ID

23696788

DOI of Published Version

10.1371/journal.pone.0062852

Start Page

e62852

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.

Keywords

OAfund

Journal Article Version

Version of Record

Published Article/Book Citation

PLoS ONE 8(5): e62852 doi:10.1371/journal.pone.0062852

Rights

Copyright: © 2013 Agarwal et al.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.

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URL

https://ir.uiowa.edu/pharmacy_pubs/2