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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 8

SHP-2 recruits PI3K to activate AKT/mTOR/S6K pathway in PDGFRα/PDGF-A–mediated tumorigenesis.

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SHP-2 recruits PI3K to activate AKT/mTOR/S6K pathway in PDGFRα/PDGF-A–me...
(A) IB analyses of serum-starved Ink4a/Arf–/– PDGFRα-expressing mAsts treated with SHP-2 inhibitors PHPS-1 or NSC87877 for 24 hours followed by 50 ng/ml PDGF-A for 5 minutes. (B) IP/IB analysis of PDGFRα-overexpressing mAsts that were transfected with SHP-2 siRNA for 48 hours and serum starved for an additional 24 hours, followed by PDGF-A stimulation. (C) IB analysis of phospho-S6 kinase levels of various mAsts stimulated by PDGF-A. (D) SHP-2 shRNAs suppressed soft agar growth of mAsts. Top: IB analysis. Bottom: Clones that had a significant decrease in SHP-2 expression (#1 and #3 in top panel) showed reduced tumor cell growth in soft agar. Data are presented as mean ± SD. *P < 0.01, Student’s t test. (E) Constitutively activated PI3K rescued the inhibitory effect of SHP-2 inhibition on blocking PDGFRα-mediated cell transformation. Left: IB analysis of expression of p110α-CAAX. Right: Soft agar assays. Data are presented as mean ± SEM. *P < 0.0001. For all IB analyses, corresponding total proteins, β-actin, or total pulled-down IgG were used as loading controls. All data are representative of 2 to 3 independent experiments.
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