SHARPIN is an endogenous inhibitor of β1-integrin activation

Juha K. Rantala, Jeroen Pouwels, Teijo Pellinen, Stefan Veltel, Petra Laasola, Elina Mattila, Christopher S. Potter, Ted Duffy, John P. Sundberg, Olli Kallioniemi, Janet A. Askari, Martin J Humphries, Maddy Parsons, Marko Salmi, Johanna Ivaska

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate β1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of β1-integrins in an RNAi screen. SHARPIN inhibited β1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased β1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin α-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of β1-integrins from inactive to active conformations. © 2011 Macmillan Publishers Limited. All rights reserved.
    Original languageEnglish
    Pages (from-to)1315-1324
    Number of pages9
    JournalNature Cell Biology
    Volume13
    Issue number11
    DOIs
    Publication statusPublished - Nov 2011

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