SHARPIN is an endogenous inhibitor of beta 1-integrin activation



: Rantala JK, Pouwels J, Pellinen T, Veltel S, Laasola P, Mattila E, Potter CS, Duffy T, Sundberg JP, Kallioniemi O, Askari JA, Humphries MJ, Parsons M, Salmi M, Ivaska J

Publisher: NATURE PUBLISHING GROUP

: 2011

: Nature Cell Biology

: NATURE CELL BIOLOGY

: NAT CELL BIOL

: 11

: 13

: 11

: 1315

: U77

: 17

: 1465-7392

DOI: https://doi.org/10.1038/ncb2340


Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate beta 1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of beta 1-integrins in an RNAi screen. SHARPIN inhibited beta 1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased beta 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 alpha-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of beta 1-integrins from inactive to active conformations.

Last updated on 2024-26-11 at 17:06