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SHARPIN is an endogenous inhibitor of β1-integrin activation

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Rantala, Juha K., Pouwels, Jeroen, Pellinen, Teijo, Veltel, Stefan, Laasola, Petra, Mattila, Elina, Potter, Christopher S., Duffy, Ted +7 more·2011·Nature Cell Biology
DOI 10.1038/ncb2340PMC PMC3257806
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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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Authors
Rantala, J. K., Pouwels, J., Pellinen, T., Veltel, S., Laasola, P., Mattila, E., Potter, C. S., Duffy, T., Sundberg, J. P., Kallioniemi, O., Askari, J. A., Humphries, M. J., Parsons, M., Salmi, M., & Ivaska, J.
Affiliations
  • VTT Technical Research Centre of Finland (FI)
  • University of Turku (FI)
  • Jackson Laboratory (US)
  • University of Helsinki (FI)
  • Wellcome Centre for Cell-Matrix Research (GB)
  • King's College London (GB)
Corresponding author
Ivaska, Johanna
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2011-09-25
Volume
13
Issue
11
Pages
1315-1324
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/ncb2340
PMC
PMC3257806
OpenAlex
W1977018102
Cited by
201
References
4
Citations by year
2026: 1 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 9 · 2021: 13 · 2020: 19 · 2019: 21 · 2018: 15 · 2017: 19 · 2016: 8 · 2015: 16 · 2014: 16 · 2013: 15 · 2012: 28
FWCI
14.43
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007449, T32 DK07449-28)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR49288, R01AR049288)
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
Keywords
SHARPIN, beta1 integrin, integrin activation, integrin inhibition, talin, kindlin, cell adhesion, leukocytes, keratinocytes, fibroblasts, RNAi screen
MeSH terms
Animals, Binding Sites, Cell Movement, Fibroblasts, Humans, Leukocytes, Ligands, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins, Protein Conformation, Recombinant Fusion Proteins, Structure-Activity Relationship, Transfection, Keratinocytes, Talin, Mice, Knockout, Integrin beta1, Protein Subunits, Protein Interaction Mapping, RNA Interference, Cell Line, Tumor, Mice, Protein Interaction Domains and Motifs

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