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

Research output: Contribution to journalArticle

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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 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

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Glioblastoma
Phosphatidylinositol 3-Kinases
Carcinogenesis
Glioma
Cyclin-Dependent Kinase Inhibitor p16
Platelet-Derived Growth Factor Receptors
Null Lymphocytes
Astrocytes
Pharmacology
Brain
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. / Liu, Kun Wei; Feng, Haizhong; Bachoo, Robert; Kazlauskas, Andrius; Smith, Erin M.; Symes, Karen; Hamilton, Ronald L.; Nagane, Motoo; Nishikawa, Ryo; Hu, Bo; Cheng, Shi Yuan.

In: Journal of Clinical Investigation, Vol. 121, No. 3, 01.03.2011, p. 905-917.

Research output: Contribution to journalArticle

Liu, KW, Feng, H, Bachoo, R, Kazlauskas, A, Smith, EM, Symes, K, Hamilton, RL, Nagane, M, Nishikawa, R, Hu, B & Cheng, SY 2011, 'SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans', Journal of Clinical Investigation, vol. 121, no. 3, pp. 905-917. https://doi.org/10.1172/JCI43690
Liu, Kun Wei ; Feng, Haizhong ; Bachoo, Robert ; Kazlauskas, Andrius ; Smith, Erin M. ; Symes, Karen ; Hamilton, Ronald L. ; Nagane, Motoo ; Nishikawa, Ryo ; Hu, Bo ; Cheng, Shi Yuan. / SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 3. pp. 905-917.
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AU - Smith, Erin M.

AU - Symes, Karen

AU - Hamilton, Ronald L.

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AU - Hu, Bo

AU - Cheng, Shi Yuan

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