dc.contributor.author | Hervieu, A | |
dc.contributor.author | Heuss, SF | |
dc.contributor.author | Zhang, C | |
dc.contributor.author | Barrow-McGee, R | |
dc.contributor.author | Joffre, C | |
dc.contributor.author | Ménard, L | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Kermorgant, S | |
dc.date.accessioned | 2020-08-28T10:29:03Z | |
dc.date.issued | 2020-06-23 | |
dc.identifier.citation | Science signaling, 2020, 13 (637) | |
dc.identifier.issn | 1945-0877 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4057 | |
dc.identifier.eissn | 1937-9145 | |
dc.identifier.doi | 10.1126/scisignal.aba8627 | |
dc.description.abstract | Receptor 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.format | Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC ADVANCEMENT SCIENCE | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.title | A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-06-02 | |
rioxxterms.versionofrecord | 10.1126/scisignal.aba8627 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2020-06-23 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Science signaling | |
pubs.issue | 637 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 13 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Molecular Addictions | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
dc.contributor.icrauthor | Hervieu Vilches, Alexia | |
dc.contributor.icrauthor | Heuss, Sara Farrah | |
dc.contributor.icrauthor | Clarke, Paul | |