SHARPIN is an endogenous inhibitor of β1-integrin activation.
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.
Mesh Terms:
Animals, Antigens, CD29, Binding Sites, Cell Line, Tumor, Cell Movement, Fibroblasts, Humans, Keratinocytes, Leukocytes, Ligands, Mice, 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
Animals, Antigens, CD29, Binding Sites, Cell Line, Tumor, Cell Movement, Fibroblasts, Humans, Keratinocytes, Leukocytes, Ligands, Mice, 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
Nat. Cell Biol.
Date: Nov. 01, 2011
PubMed ID: 21947080
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