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- Title
SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans.
- Authors
Kun-Wei Liu; Haizhong Feng; Bachoo, Robert; Kazlauskas, Andrius; Smith, Erin M.; Symes, Karen; Hamilton, Ronald L.; Nagane, Motoo; Nishikawa, Ryo; Bo Hu; Shi-Yuan Cheng; Liu, Kun-Wei; Feng, Haizhong; Hu, Bo; Cheng, Shi-Yuan
- 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 coexpressed 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.
- Subjects
GLIOBLASTOMA multiforme; PLATELET-derived growth factor; CYCLIN-dependent kinases; ASTROCYTES; LABORATORY mice
- Publication
Journal of Clinical Investigation, 2011, Vol 121, Issue 3, p905
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI43690