title: LNK (SH2B3) is a key regulator of integrin signaling in endothelial cells and targets α-parvin to control cell adhesion and migration.
abstract: Focal adhesion (FA) formation and disassembly play an essential role in adherence and migration of endothelial cells. These processes are highly regulated and involve various signaling molecules that are not yet completely identified. Lnk [Src homology 2-B3 (SH2B3)] belongs to a family of SH2-containing proteins with important adaptor functions. In this study, we showed that Lnk distribution follows that of vinculin, localizing Lnk in FAs. Inhibition of Lnk by RNA interference resulted in decreased spreading, whereas sustained expression dramatically increases the number of focal and cell-matrix adhesions. We demonstrated that Lnk expression impairs FA turnover and cell migration and regulates β1-integrin-mediated signaling via Akt and GSK3β phosphorylation. Moreover, the α-parvin protein was identified as one of the molecular targets of Lnk responsible for impaired FA dynamics and cell migration. Finally, we established the ILK protein as a new molecular partner for Lnk and proposed a model in which Lnk regulates α-parvin expression through its interaction with ILK. Collectively, our results underline the adaptor Lnk as a novel and effective key regulator of integrin-mediated signaling controlling endothelial cell adhesion and migration.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 643, Nantes, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Devallière
authors.forename: Mathias
authors.initials: M
authors.lastname: Chatelais
authors.forename: Juliette
authors.initials: J
authors.lastname: Fitau
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gérard
authors.forename: Philippe
authors.initials: P
authors.lastname: Hulin
authors.forename: Laura
authors.initials: L
authors.lastname: Velazquez
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Turner
authors.forename: Béatrice
authors.initials: B
authors.lastname: Charreau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D021982:Cell-Matrix Junctions / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000099200:Scaffold Protein ILK; D000096985:Calponins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019012:Integrin beta1; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D000099200:Scaffold Protein ILK; C486590:PARVA protein, human; D000096985:Calponins; C490778:SH2B3 protein, human