SHARPIN is an endogenous inhibitor of β1-integrin activation

Juha K. Rantala, Jeroen Pouwels, Teijo Pellinen, Stefan Veltel, Petra Laasola, Elina Mattila, Christopher S. Potter, Ted Duffy, John P. Sundberg, Olli Kallioniemi, Janet A. Askari, Martin J. Humphries, Maddy Parsons, Marko Salmi, Johanna Ivaska (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

133 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1315-1324
JournalNature Cell Biology
Volume13
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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