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Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis

Author

Listed:
  • Severa Bunda

    (University of Toronto, 1 King’s College Circle)

  • Kelly Burrell

    (Brain Tumour Research Centre, Hospital for Sick Children, University Health Network, Toronto Medical Discovery Tower)

  • Pardeep Heir

    (University of Toronto, 1 King’s College Circle)

  • Lifan Zeng

    (School of Medicine, Indiana University)

  • Amir Alamsahebpour

    (Brain Tumour Research Centre, Hospital for Sick Children, University Health Network, Toronto Medical Discovery Tower)

  • Yoshihito Kano

    (University of Toronto, 1 King’s College Circle
    University of Toronto, 1 King’s College Circle)

  • Brian Raught

    (Princess Margaret Cancer Centre, Toronto Medical Discovery Tower)

  • Zhong-Yin Zhang

    (School of Medicine, Indiana University)

  • Gelareh Zadeh

    (Brain Tumour Research Centre, Hospital for Sick Children, University Health Network, Toronto Medical Discovery Tower)

  • Michael Ohh

    (University of Toronto, 1 King’s College Circle
    University of Toronto, 1 King’s College Circle)

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.

Suggested Citation

  • Severa Bunda & Kelly Burrell & Pardeep Heir & Lifan Zeng & Amir Alamsahebpour & Yoshihito Kano & Brian Raught & Zhong-Yin Zhang & Gelareh Zadeh & Michael Ohh, 2015. "Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9859
    DOI: 10.1038/ncomms9859
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    Cited by:

    1. Ziyuan Jiang & Anne E. van Vlimmeren & Deepti Karandur & Alyssa Semmelman & Neel H. Shah, 2025. "Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    2. Teklab Gebregiworgis & Yoshihito Kano & Jonathan St-Germain & Nikolina Radulovich & Molly L. Udaskin & Ahmet Mentes & Richard Huang & Betty P. K. Poon & Wenguang He & Ivette Valencia-Sama & Claire M. , 2021. "The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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