title: Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration.
abstract: The small GTPase Rac1 has been implicated in the formation and dissemination of tumours. Upon activation by guanine nucleotide exchange factors (GEFs), Rac1 associates with a variety of proteins in the cell thereby regulating various functions, including cell migration. However, activation of Rac1 can lead to opposing migratory phenotypes raising the possibility of exacerbating tumour progression when targeting Rac1 in a clinical setting. This calls for the identification of factors that influence Rac1-driven cell motility. Here we show that Tiam1 and P-Rex1, two Rac GEFs, promote Rac1 anti- and pro-migratory signalling cascades, respectively, through regulating the Rac1 interactome. In particular, we demonstrate that P-Rex1 stimulates migration through enhancing the interaction between Rac1 and the actin-remodelling protein flightless-1 homologue, to modulate cell contraction in a RhoA-ROCK-independent manner.
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M204BX, UK.
authors.forename: Hadir
authors.initials: H
authors.lastname: Marei
authors.affiliation: Proteome Center Tuebingen, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen 72026, Germany.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Carpy
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M204BX, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Woroniuk
authors.affiliation: Invasion and Metastasis Group, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Vennin
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M204BX, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: White
authors.affiliation: Invasion and Metastasis Group, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: Proteome Center Tuebingen, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen 72026, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Macek
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M204BX, UK.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Malliri
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D015534:Trans-Activators; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D002352:Carrier Proteins; C000609263:FlII protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; C511197:PREX1 protein, mouse; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D015534:Trans-Activators; D020830:rac1 GTP-Binding Protein