title: Mammalian diaphanous-related formin 1 regulates GSK3β-dependent microtubule dynamics required for T cell migratory polarization.
abstract: The mammalian diaphanous-related formin (mDia1), a Rho-regulated cytoskeletal modulator, has been shown to promote T lymphocyte chemotaxis and interaction with antigen presenting cells, but the mechanisms underpinning mDia1 roles in these processes have not been defined. Here we show that mDia1(-/-) T cells exhibit impaired lymphocyte function-associated antigen 1 (LFA-1)-mediated T cell adhesion, migration and in vivo trafficking. These defects are associated with impaired microtubule (MT) polarization and stabilization, altered MT dynamics and reduced peripheral clustering of the MT plus-end-protein, adenomatous polyposis coli (APC) in migrating T cells following LFA-1-engagement. Loss of mDia1 also leads to impaired inducible inactivation of the glycogen synthase kinase (GSK) 3β as well as hyperphosphorylation and reduced levels of APC in migrating T cells. These findings identify essential roles for the mDia1 formin in modulating GSK3β-dependent MT contributions to induction of T-cell polarity, adhesion and motility.
authors.affiliation: Departments of Immunology and Molecular Genetics, University of Toronto, Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institutes, Toronto, Ontario, Canada ; Department of Hematology, Xijing Hospital, Xian, Shaanxi, China.
authors.forename: Baoxia
authors.initials: B
authors.lastname: Dong
authors.forename: Steven S
authors.initials: SS
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Gao
authors.forename: Haichun
authors.initials: H
authors.lastname: Su
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Fuzi
authors.initials: F
authors.lastname: Jin
authors.forename: Ajay
authors.initials: A
authors.lastname: Bhargava
authors.forename: Xiequn
authors.initials: X
authors.lastname: Chen
authors.forename: Lars
authors.initials: L
authors.lastname: Jorgensen
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Alberts
authors.forename: Jinyi
authors.initials: J
authors.lastname: Zhang
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
mesh_terms: D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation; D000080865:Formins; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3