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 and Michael Ohh ()
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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
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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9859

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