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dc.contributor.authorHervieu, A
dc.contributor.authorHeuss, SF
dc.contributor.authorZhang, C
dc.contributor.authorBarrow-McGee, R
dc.contributor.authorJoffre, C
dc.contributor.authorMénard, L
dc.contributor.authorClarke, PA
dc.contributor.authorKermorgant, S
dc.date.accessioned2020-08-28T10:29:03Z
dc.date.issued2020-06-23
dc.identifier.citationScience signaling, 2020, 13 (637)
dc.identifier.issn1945-0877
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4057
dc.identifier.eissn1937-9145
dc.identifier.doi10.1126/scisignal.aba8627
dc.description.abstractReceptor tyrosine kinases (RTKs) are often overexpressed or mutated in cancers and drive tumor growth and metastasis. In the current model of RTK signaling, including that of MET, downstream phosphatidylinositol 3-kinase (PI3K) mediates both cell proliferation and cell migration, whereas the small guanosine triphosphatase (GTPase) Rac1 mediates cell migration. However, in cultured NIH3T3 and glioblastoma cells, we found that class I PI3K mediated oncogenic MET-induced cell migration but not anchorage-independent growth. In contrast, Rac1 regulated both processes in distinct ways. Downstream of PI3K, Rac1 mediated cell migration through its GTPase activity, whereas independently of PI3K, Rac1 mediated anchorage-independent growth in a GTPase-independent manner through an adaptor function. Through its RKR motif, Rac1 formed a complex with the kinase mTOR to promote its translocation to the plasma membrane, where its activity promoted anchorage-independent growth of the cell cultures. Inhibiting mTOR with rapamycin suppressed the growth of subcutaneous MET-mutant cell grafts in mice, including that of MET inhibitor-resistant cells. These findings reveal a GTPase-independent role for Rac1 in mediating a PI3K-independent MET-to-mTOR pathway and suggest alternative or combined strategies that might overcome resistance to RTK inhibitors in patients with cancer.
dc.formatElectronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.titleA PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration.
dc.typeJournal Article
dcterms.dateAccepted2020-06-02
rioxxterms.versionofrecord10.1126/scisignal.aba8627
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2020-06-23
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScience signaling
pubs.issue637
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Addictions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Addictions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.publication-statusPublished
pubs.volume13en_US
pubs.embargo.termsNot known
icr.researchteamMolecular Addictionsen_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
dc.contributor.icrauthorHervieu Vilches, Alexiaen
dc.contributor.icrauthorHeuss, Sara Farrahen
dc.contributor.icrauthorClarke, Paulen


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