title: Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis.
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.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, M5S1A8 Ontario, Canada.
authors.forename: Severa
authors.initials: S
authors.lastname: Bunda
authors.affiliation: Brain Tumour Research Centre, Hospital for Sick Children, University Health Network, Toronto Medical Discovery Tower, 101 College Street, East Tower, Toronto, M5G1L7 Ontario, Canada.
authors.forename: Kelly
authors.initials: K
authors.lastname: Burrell
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, M5S1A8 Ontario, Canada.
authors.forename: Pardeep
authors.initials: P
authors.lastname: Heir
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.
authors.forename: Lifan
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Brain Tumour Research Centre, Hospital for Sick Children, University Health Network, Toronto Medical Discovery Tower, 101 College Street, East Tower, Toronto, M5G1L7 Ontario, Canada.
authors.forename: Amir
authors.initials: A
authors.lastname: Alamsahebpour
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, M5S1A8 Ontario, Canada.|Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, M5S1A8 Ontario, Canada.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kano
authors.affiliation: Princess Margaret Cancer Centre, Toronto Medical Discovery Tower, 9-701A, 101 College Street, Toronto, M5G1L7 Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Raught
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Brain Tumour Research Centre, Hospital for Sick Children, University Health Network, Toronto Medical Discovery Tower, 101 College Street, East Tower, Toronto, M5G1L7 Ontario, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, M5S1A8 Ontario, Canada.|Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, M5S1A8 Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Ohh
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002460:Cell Line; D005260:Female; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*
chemical_list: D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D015689:Oncogene Protein p21(ras)