SHARPIN is an endogenous inhibitor of β1-integrin activation

Nat Cell Biol. 2011 Sep 25;13(11):1315-24. doi: 10.1038/ncb2340.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement
  • Fibroblasts / metabolism
  • Humans
  • Integrin beta1 / chemistry
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Keratinocytes / metabolism
  • Leukocytes / metabolism
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Interaction Mapping
  • Protein Subunits
  • RNA Interference
  • Recombinant Fusion Proteins / metabolism
  • Structure-Activity Relationship
  • Talin / metabolism
  • Transfection


  • Integrin beta1
  • Ligands
  • Nerve Tissue Proteins
  • Protein Subunits
  • Recombinant Fusion Proteins
  • Talin
  • sharpin