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SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans
Kun-Wei Liu, … , Bo Hu, Shi-Yuan Cheng
Kun-Wei Liu, … , Bo Hu, Shi-Yuan Cheng
Published February 14, 2011
Citation Information: J Clin Invest. 2011;121(3):905-917. https://doi.org/10.1172/JCI43690.
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Research Article Oncology

SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans

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Abstract

Recent collaborative efforts have subclassified malignant glioblastomas into 4 clinical relevant subtypes based on their signature genetic lesions. Platelet-derived growth factor receptor α (PDGFRA) overexpression is concomitant with a loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of glioblastomas. Here we report that activation of PDGFRα conferred tumorigenicity to Ink4a/Arf-deficient mouse astrocytes and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF suppressed PDGFRα-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFRα that lost capacity to bind to SHP-2 or PI3K significantly diminished PDGFRα-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFRα, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. PDGFRα and PDGF-A are co-expressed in clinical glioblastoma specimens, and such co-expression is linked with activation of SHP-2/AKT/mTOR signaling. Together, our data suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFRα promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity. These findings functionally validate the genomic analysis of glioblastomas and identify SHP-2 as a potential target for treatment of glioblastomas.

Authors

Kun-Wei Liu, Haizhong Feng, Robert Bachoo, Andrius Kazlauskas, Erin M. Smith, Karen Symes, Ronald L. Hamilton, Motoo Nagane, Ryo Nishikawa, Bo Hu, Shi-Yuan Cheng

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Figure 5

Impacts of PDGFRα mutations on downstream signaling of PDGFRα and anchorage-independent growth in soft agar of Ink4a/Arf–/– mAsts.

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Impacts of PDGFRα mutations on downstream signaling of PDGFRα and anchor...
(A) Schematics of various PDGFRα mutants. (B) IB analyses of PDGF-A–stimulated Ink4a/Arf–/– mAsts overexpressing individual PDGFRα mutants. Corresponding total proteins or β-actin were used as loading controls. Vertical lines in left panels of p-Tyr, PDGFRα, and β-actin indicate that these images were modified by removal of two lanes of samples between WT and R627. The longer white vertical line indicates that the samples were analyzed in separate SDS-PAGE gels due to the limit of sample loading per gel. (C and D) Soft agar assay. (C) Representative images of soft agar colonies. (D) Quantification of soft agar assays. Data are presented as mean ± SD and are representative of 2 independent experiments. Scale bars: 1 mm. *P < 0.01.
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