title: Tyrosine phosphorylation of the Gα-interacting protein GIV promotes activation of phosphoinositide 3-kinase during cell migration.
abstract: GIV (Gα-interacting vesicle-associated protein; also known as Girdin) enhances Akt activation downstream of multiple growth factor- and G protein (heterotrimeric guanosine 5'-triphosphate-binding protein)-coupled receptors to trigger cell migration and cancer invasion. We demonstrate that GIV is a tyrosine phosphoprotein that directly binds to and activates phosphoinositide 3-kinase (PI3K). Upon ligand stimulation of various receptors, GIV was phosphorylated at tyrosine-1764 and tyrosine-1798 by both receptor and non-receptor tyrosine kinases. These phosphorylation events enabled direct binding of GIV to the amino- and carboxyl-terminal Src homology 2 domains of p85α, a regulatory subunit of PI3K; stabilized receptor association with PI3K; and enhanced PI3K activity at the plasma membrane to trigger cell migration. Tyrosine phosphorylation of GIV and its association with p85α increased during metastatic progression of a breast carcinoma. These results suggest a mechanism by which multiple receptors activate PI3K through tyrosine phosphorylation of GIV, thereby making the GIV-PI3K interaction a potential therapeutic target within the PI3K-Akt pathway.
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Lin
authors.forename: Jason
authors.initials: J
authors.lastname: Ear
authors.forename: Yelena
authors.initials: Y
authors.lastname: Pavlova
authors.forename: Yash
authors.initials: Y
authors.lastname: Mittal
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Majid
authors.initials: M
authors.lastname: Ghassemian
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Mikel
authors.initials: M
authors.lastname: Garcia-Marcos
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D000704:Analysis of Variance; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002853:Chromatography, Liquid; D004789:Enzyme Activation / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D008840:Microfilament Proteins / Q000378:metabolism*; D008958:Models, Molecular; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D053719:Tandem Mass Spectrometry; D014443:Tyrosine / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D014443:Tyrosine; D058539:Phosphatidylinositol 3-Kinase