SHARPIN is an endogenous inhibitor of ?1-integrin activation.

ABSTRACT: Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate ?1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of ?1-integrins in an RNAi screen. SHARPIN inhibited ?1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased ?1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin ?-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of ?1-integrins from inactive to active conformations.

SUBMITTER: Rantala JK 

PROVIDER: S-EPMC3257806 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature