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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)905-917
Number of pages13
JournalJournal of Clinical Investigation
Volume121
Issue number3
DOIs
StatePublished - Mar 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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    Liu, K. W., Feng, H., Bachoo, R., Kazlauskas, A., Smith, E. M., Symes, K., Hamilton, R. L., Nagane, M., Nishikawa, R., Hu, B., & Cheng, S. Y. (2011). SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. Journal of Clinical Investigation, 121(3), 905-917. https://doi.org/10.1172/JCI43690