title: Focal adhesions are foci for tyrosine-based signal transduction via GIV/Girdin and G proteins.
abstract: GIV/Girdin is a multimodular signal transducer and a bona fide metastasis-related protein. As a guanidine exchange factor (GEF), GIV modulates signals initiated by growth factors (chemical signals) by activating the G protein Gαi. Here we report that mechanical signals triggered by the extracellular matrix (ECM) also converge on GIV-GEF via β1 integrins and that focal adhesions (FAs) serve as the major hubs for mechanochemical signaling via GIV. GIV interacts with focal adhesion kinase (FAK) and ligand-activated β1 integrins. Phosphorylation of GIV by FAK enhances PI3K-Akt signaling, the integrity of FAs, increases cell-ECM adhesion, and triggers ECM-induced cell motility. Activation of Gαi by GIV-GEF further potentiates FAK-GIV-PI3K-Akt signaling at the FAs. Spatially restricted signaling via tyrosine phosphorylated GIV at the FAs is enhanced during cancer metastasis. Thus GIV-GEF serves as a unifying platform for integration and amplification of adhesion (mechanical) and growth factor (chemical) signals during cancer progression.
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093 inmalopezsanchez@hotmail.com prghosh@ucsd.edu.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Lopez-Sanchez
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kalogriopoulos
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: I-Chung
authors.initials: IC
authors.lastname: Lo
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Firooz
authors.initials: F
authors.lastname: Kabir
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Midde
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Honghui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093 Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093 inmalopezsanchez@hotmail.com prghosh@ucsd.edu.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: C502451:CCDC88A protein, human; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go