SHARPIN is an endogenous inhibitor of beta 1-integrin activation
Rantala JK; Salmi M; Askari JA; Duffy T; Ivaska J; Sundberg JP; Parsons M; Kallioniemi O; Laasola P; Veltel S; Mattila E; Pellinen T; Humphries MJ; Pouwels J; Potter CS
SHARPIN is an endogenous inhibitor of beta 1-integrin activation
Rantala JK
Salmi M
Askari JA
Duffy T
Ivaska J
Sundberg JP
Parsons M
Kallioniemi O
Laasola P
Veltel S
Mattila E
Pellinen T
Humphries MJ
Pouwels J
Potter CS
NATURE PUBLISHING GROUP
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042715347
https://urn.fi/URN:NBN:fi-fe2021042715347
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]