title: RCP-driven α5β1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex.
abstract: Inhibition of αvβ3 or expression of mutant p53 promotes invasion into fibronectin (FN)-containing extracellular matrix (ECM) by enhancing Rab-coupling protein (RCP)-dependent recycling of α5β1 integrin. RCP and α5β1 cooperatively recruit receptor tyrosine kinases, including EGFR1, to regulate their trafficking and downstream signaling via protein kinase B (PKB)/Akt, which, in turn, promotes invasive migration. In this paper, we identify a novel PKB/Akt substrate, RacGAP1, which is phosphorylated as a consequence of RCP-dependent α5β1 trafficking. Phosphorylation of RacGAP1 promotes its recruitment to IQGAP1 at the tips of invasive pseudopods, and RacGAP1 then locally suppresses the activity of the cytoskeletal regulator Rac and promotes the activity of RhoA in this subcellular region. This Rac to RhoA switch promotes the extension of pseudopodial processes and invasive migration into FN-containing matrices, in a RhoA-dependent manner. Thus, the localized endocytic trafficking of α5β1 within the tips of invasive pseudopods elicits signals that promote the reorganization of the actin cytoskeleton, protrusion, and invasion into FN-rich ECM.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, M13 9PT Manchester, England, UK.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquemet
authors.forename: David M
authors.initials: DM
authors.lastname: Green
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Bridgewater
authors.forename: Alexander
authors.initials: A
authors.lastname: von Kriegsheim
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Humphries
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Caswell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; C101203:IQ motif containing GTPase activating protein 1; D039081:Integrin alpha5beta1; D008565:Membrane Proteins; C488966:RAB11FIP1 protein, human; C115995:mgcRacGAP; D020703:ras GTPase-Activating Proteins; C066737:RHOA protein, human; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
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