Mammalian diaphanous-related formin 1 regulates GSK3β-dependent microtubule dynamics required for T cell migratory polarization

PLoS One. 2013 Nov 18;8(11):e80500. doi: 10.1371/journal.pone.0080500. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Movement* / genetics
  • Cell Movement* / immunology
  • Cell Polarity / genetics
  • Cell Polarity / immunology
  • Enzyme Activation
  • Formins
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lymphocyte Activation / immunology
  • Lymphocyte Function-Associated Antigen-1 / genetics
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Mice
  • Mice, Knockout
  • Microtubules / metabolism*
  • Phosphorylation
  • Protein Binding
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • Adenomatous Polyposis Coli Protein
  • Carrier Proteins
  • Diap1 protein, mouse
  • Formins
  • Lymphocyte Function-Associated Antigen-1
  • Intercellular Adhesion Molecule-1
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3