A1 Refereed original research article in a scientific journal
SHARPIN is an endogenous inhibitor of beta 1-integrin activation
Authors: 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
Publication year: 2011
Journal: Nature Cell Biology
Journal name in source: NATURE CELL BIOLOGY
Journal acronym: NAT CELL BIOL
Number in series: 11
Volume: 13
Issue: 11
First page : 1315
Last page: U77
Number of pages: 17
ISSN: 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.
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