SHARPIN is an endogenous inhibitor of beta1-integrin activation.
Document Type
Article
Publication Date
2011
Keywords
Antigens-CD29, Binding-Sites, Cell-Line-Tumor, Cell-Movement, Fibroblasts, Humans, Keratinocytes, Leukocytes, Ligands, Mice-Inbred-C57BL, Mice-Knockout, Mutation, Nerve-Tissue-Proteins, Protein-Conformation, Protein-Interaction-Domains-and-Motifs, Protein-Interaction-Mapping, Protein-Subunits, RNA-Interference, Recombinant-Fusion-Proteins, Structure-Activity-Relationship, Talin, Transfection
JAX Source
Nat-Cell-Biol 2011 Nov; 13(11):1315-24.
First Page
1315
Last Page
1324
Abstract
Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate beta1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of beta1-integrins in an RNAi screen. SHARPIN inhibited beta1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased beta1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin alpha-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of beta1-integrins from inactive to active conformations.
Recommended Citation
Rantala JK,
Pouwels J,
Pellinen T,
Veltel S,
Laasola P,
Mattila E,
Potter CS,
Duffy T,
Sundberg JP,
et a.
SHARPIN is an endogenous inhibitor of beta1-integrin activation. Nat-Cell-Biol 2011 Nov; 13(11):1315-24.