title: Integrins activate trimeric G proteins via the nonreceptor protein GIV/Girdin.
abstract: Signal transduction via integrins and G protein-coupled receptors is critical to control cell behavior. These two receptor classes have been traditionally believed to trigger distinct and independent signaling cascades in response to extracellular cues. Here, we report a novel mechanism of integrin signaling that requires activation of the trimeric G protein Gαi by the nonreceptor guanine nucleotide exchange factor (GEF) GIV (also known as Girdin), a metastasis-associated protein. We demonstrate that GIV enhances integrin-dependent cell responses upon extracellular matrix stimulation and makes tumor cells more invasive. These responses include remodeling of the actin cytoskeleton and PI3K-dependent signaling, resulting in enhanced haptotaxis and invasion. We show that both GIV and its substrate Gαi3 are recruited to active integrin complexes and that tumor cells engineered to express GEF-deficient GIV fail to transduce integrin signals into proinvasive responses via a Gβγ-PI3K axis. Our discoveries delineate a novel mechanism by which integrin signaling is rewired during metastasis to result in increased tumor invasiveness.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Anthony
authors.initials: A
authors.lastname: Leyme
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Arthur
authors.initials: A
authors.lastname: Marivin
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Lorena
authors.initials: L
authors.lastname: Perez-Gutierrez
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Lien T
authors.initials: LT
authors.lastname: Nguyen
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118 mgm1@bu.edu.
authors.forename: Mikel
authors.initials: M
authors.lastname: Garcia-Marcos
mesh_terms: D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D016023:Integrins; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D033921:Vesicular Transport Proteins; C502451:CCDC88A protein, human; C527550:Ccdc88a protein, mouse; C498819:GNAI3 protein, human; C417708:Gnai3 protein, mouse