title: Endothelial cell migration on fibronectin is regulated by syntaxin 6-mediated alpha5beta1 integrin recycling.
abstract: The α5β1 integrin heterodimer regulates many processes that contribute to embryonic development and angiogenesis, in both physiological and pathological contexts. As one of the major adhesion complexes on endothelial cells, it plays a vital role in adhesion and migration along the extracellular matrix. We recently showed that angiogenesis is modulated by syntaxin 6, a Golgi- and endosome-localized t-SNARE, and that it does so by regulating the post-Golgi trafficking of VEGFR2. Here we show that syntaxin 6 is also required for α5β1 integrin-mediated adhesion of endothelial cells to, and migration along, fibronectin. We demonstrate that syntaxin 6 and α5β1 integrin colocalize in EEA1-containing early endosomes, and that functional inhibition of syntaxin 6 leads to misrouting of β1 integrin to the degradation pathway (late endosomes and lysosomes) rather transport along recycling pathway from early endosomes; an increase in the pool of ubiquitinylated α5 integrin and its lysosome-dependent degradation; reduced cell spreading on fibronectin; decreased Rac1 activation; and altered Rac1 localization. Collectively, our data show that functional syntaxin 6 is required for the regulation of α5β1-mediated endothelial cell movement on fibronectin. These syntaxin 6-regulated membrane trafficking events control outside-in signaling via haptotactic and chemotactic mechanisms.
authors: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Ajit
authors: A
authors: Tiwari
authors: Jae-Joon
authors: JJ
authors: Jung
authors: Shivangi M
authors: SM
authors: Inamdar
authors: Charles O
authors: CO
authors: Brown
authors: Apollina
authors: A
authors: Goel
authors: Amit
authors: A
authors: Choudhury
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005353:Fibronectins; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D059748:Proteolysis; D050765:Qa-SNARE Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D005353:Fibronectins; D039482:Integrin alpha5; D019012:Integrin beta1; D050765:Qa-SNARE Proteins; C107953:RAC1 protein, human; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D020830:rac1 GTP-Binding Protein