Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis

Severa Bunda, Kelly Burrell, Pardeep Heir, Lifan Zeng, Amir Alamsahebpour, Yoshihito Kano, Brian Raught, Zhong Yin Zhang, Gelareh Zadeh, Michael Ohh

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61 Scopus citations

Abstract

Ras is phosphorylated on a conserved tyrosine at position 32 within the switch I region via Src kinase. This phosphorylation inhibits the binding of effector Raf while promoting the engagement of GTPase-activating protein (GAP) and GTP hydrolysis. Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. In comparison to normal astrocytes, SHP2 activity is elevated in astrocytes isolated from glioblastoma multiforme (GBM)-prone H-Ras(12V) knock-in mice as well as in glioma cell lines and patient-derived GBM specimens exhibiting hyperactive Ras. Pharmacologic inhibition of SHP2 activity attenuates cell proliferation, soft-agar colony formation and orthotopic GBM growth in NOD/SCID mice and decelerates the progression of low-grade astrocytoma to GBM in a spontaneous transgenic glioma mouse model. These results identify SHP2 as a direct activator of Ras and a potential therapeutic target for cancers driven by a previously 'undruggable' oncogenic or hyperactive Ras.

Original languageEnglish (US)
Article number8859
JournalNature communications
Volume6
DOIs
StatePublished - Nov 30 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Bunda, S., Burrell, K., Heir, P., Zeng, L., Alamsahebpour, A., Kano, Y., Raught, B., Zhang, Z. Y., Zadeh, G., & Ohh, M. (2015). Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. Nature communications, 6, [8859]. https://doi.org/10.1038/ncomms9859