A crucial role for β2 integrins in podosome formation, dynamics and Toll-like-receptor-signaled disassembly in dendritic cells

Christian Gawden-Bone, Michele A. West, Vicky L. Morrison, Alexander J. Edgar, Sarah J. McMillan, Brian D. Dill, Matthias Trost, Alan Prescott, Susanna C. Fagerholm, Colin Watts (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    13 Citations (Scopus)

    Abstract

    The dynamic properties of podosomes, their ability to degrade the underlying matrix and their modulation by Toll-like receptor (TLR) signaling in dendritic cells (DCs) suggests they have an important role in migration. Integrins are thought to participate in formation and dynamics of podosomes but the multiplicity of integrins in podosomes has made this difficult to assess. We report that murine DCs that lack β2 integrins fail to form podosomes. Re-expression of β2 integrins restored podosomes but not when the membrane proximal or distal NPxF motifs, or when an intervening triplet of threonine residues were mutated. We show that β2 integrins are remarkably long-lived in podosome clusters and form a persistent framework that hosts multiple actin-core-formation events at the same or adjacent sites. When β2 integrin amino acid residues 745 or 756 were mutated from Ser to Ala, podosomes became resistant to dissolution mediated through TLR signaling. TLR signaling did not detectably modulate phosphorylation at these sites but mutation of either residue to phospho-mimetic Asp increased β2 integrin turnover in podosomes, indicating that phosphorylation at one or both sites establishes permissive conditions for TLR-signaled podosome disassembly.
    Original languageEnglish
    Pages (from-to)4213-4224
    Number of pages12
    JournalJournal of Cell Science
    Volume127
    Issue number19
    Early online date1 Aug 2014
    DOIs
    Publication statusPublished - 1 Oct 2014

    Fingerprint

    Toll-Like Receptors
    Integrins
    Dendritic Cells
    Phosphorylation
    Podosomes
    Threonine
    Actins
    Amino Acids
    Mutation
    Membranes

    Cite this

    Gawden-Bone, Christian ; West, Michele A. ; Morrison, Vicky L. ; Edgar, Alexander J. ; McMillan, Sarah J. ; Dill, Brian D. ; Trost, Matthias ; Prescott, Alan ; Fagerholm, Susanna C. ; Watts, Colin. / A crucial role for β2 integrins in podosome formation, dynamics and Toll-like-receptor-signaled disassembly in dendritic cells. In: Journal of Cell Science. 2014 ; Vol. 127, No. 19. pp. 4213-4224.
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    abstract = "The dynamic properties of podosomes, their ability to degrade the underlying matrix and their modulation by Toll-like receptor (TLR) signaling in dendritic cells (DCs) suggests they have an important role in migration. Integrins are thought to participate in formation and dynamics of podosomes but the multiplicity of integrins in podosomes has made this difficult to assess. We report that murine DCs that lack β2 integrins fail to form podosomes. Re-expression of β2 integrins restored podosomes but not when the membrane proximal or distal NPxF motifs, or when an intervening triplet of threonine residues were mutated. We show that β2 integrins are remarkably long-lived in podosome clusters and form a persistent framework that hosts multiple actin-core-formation events at the same or adjacent sites. When β2 integrin amino acid residues 745 or 756 were mutated from Ser to Ala, podosomes became resistant to dissolution mediated through TLR signaling. TLR signaling did not detectably modulate phosphorylation at these sites but mutation of either residue to phospho-mimetic Asp increased β2 integrin turnover in podosomes, indicating that phosphorylation at one or both sites establishes permissive conditions for TLR-signaled podosome disassembly.",
    author = "Christian Gawden-Bone and West, {Michele A.} and Morrison, {Vicky L.} and Edgar, {Alexander J.} and McMillan, {Sarah J.} and Dill, {Brian D.} and Matthias Trost and Alan Prescott and Fagerholm, {Susanna C.} and Colin Watts",
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    Gawden-Bone, C, West, MA, Morrison, VL, Edgar, AJ, McMillan, SJ, Dill, BD, Trost, M, Prescott, A, Fagerholm, SC & Watts, C 2014, 'A crucial role for β2 integrins in podosome formation, dynamics and Toll-like-receptor-signaled disassembly in dendritic cells', Journal of Cell Science, vol. 127, no. 19, pp. 4213-4224. https://doi.org/10.1242/jcs.151167

    A crucial role for β2 integrins in podosome formation, dynamics and Toll-like-receptor-signaled disassembly in dendritic cells. / Gawden-Bone, Christian; West, Michele A.; Morrison, Vicky L.; Edgar, Alexander J.; McMillan, Sarah J.; Dill, Brian D.; Trost, Matthias; Prescott, Alan ; Fagerholm, Susanna C.; Watts, Colin (Lead / Corresponding author).

    In: Journal of Cell Science, Vol. 127, No. 19, 01.10.2014, p. 4213-4224.

    Research output: Contribution to journalArticle

    TY - JOUR

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    AU - Gawden-Bone, Christian

    AU - West, Michele A.

    AU - Morrison, Vicky L.

    AU - Edgar, Alexander J.

    AU - McMillan, Sarah J.

    AU - Dill, Brian D.

    AU - Trost, Matthias

    AU - Prescott, Alan

    AU - Fagerholm, Susanna C.

    AU - Watts, Colin

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    N2 - The dynamic properties of podosomes, their ability to degrade the underlying matrix and their modulation by Toll-like receptor (TLR) signaling in dendritic cells (DCs) suggests they have an important role in migration. Integrins are thought to participate in formation and dynamics of podosomes but the multiplicity of integrins in podosomes has made this difficult to assess. We report that murine DCs that lack β2 integrins fail to form podosomes. Re-expression of β2 integrins restored podosomes but not when the membrane proximal or distal NPxF motifs, or when an intervening triplet of threonine residues were mutated. We show that β2 integrins are remarkably long-lived in podosome clusters and form a persistent framework that hosts multiple actin-core-formation events at the same or adjacent sites. When β2 integrin amino acid residues 745 or 756 were mutated from Ser to Ala, podosomes became resistant to dissolution mediated through TLR signaling. TLR signaling did not detectably modulate phosphorylation at these sites but mutation of either residue to phospho-mimetic Asp increased β2 integrin turnover in podosomes, indicating that phosphorylation at one or both sites establishes permissive conditions for TLR-signaled podosome disassembly.

    AB - The dynamic properties of podosomes, their ability to degrade the underlying matrix and their modulation by Toll-like receptor (TLR) signaling in dendritic cells (DCs) suggests they have an important role in migration. Integrins are thought to participate in formation and dynamics of podosomes but the multiplicity of integrins in podosomes has made this difficult to assess. We report that murine DCs that lack β2 integrins fail to form podosomes. Re-expression of β2 integrins restored podosomes but not when the membrane proximal or distal NPxF motifs, or when an intervening triplet of threonine residues were mutated. We show that β2 integrins are remarkably long-lived in podosome clusters and form a persistent framework that hosts multiple actin-core-formation events at the same or adjacent sites. When β2 integrin amino acid residues 745 or 756 were mutated from Ser to Ala, podosomes became resistant to dissolution mediated through TLR signaling. TLR signaling did not detectably modulate phosphorylation at these sites but mutation of either residue to phospho-mimetic Asp increased β2 integrin turnover in podosomes, indicating that phosphorylation at one or both sites establishes permissive conditions for TLR-signaled podosome disassembly.

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    JF - Journal of Cell Science

    SN - 0021-9533

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