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Nat Cell Biol. 2011 Sep 25;13(11):1315-24. doi: 10.1038/ncb2340.

SHARPIN is an endogenous inhibitor of β1-integrin activation.

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1
Medical Biotechnology, VTT Technical Research Centre of Finland, 20521 Turku, Finland.

Abstract

Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate β1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of β1-integrins in an RNAi screen. SHARPIN inhibited β1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased β1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin α-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of β1-integrins from inactive to active conformations.

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PMID:
21947080
PMCID:
PMC3257806
DOI:
10.1038/ncb2340
[Indexed for MEDLINE]
Free PMC Article

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