SHARPIN is an endogenous inhibitor of beta1-integrin activation.
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
Nat-Cell-Biol 2011 Nov; 13(11):1315-24.
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.
Rantala, J K.; Pouwels, J; Pellinen, T; Veltel, S; Laasola, P; Mattila, E; Potter, C S.; Duffy, T; Sundberg, J P.; and et, al, "SHARPIN is an endogenous inhibitor of beta1-integrin activation." (2011). Faculty Research 2011. 92.