Sharpin is an endogenous inhibitor of β1-integrin activation

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS TALIN AND KINDLIN USE INTEGRIN TAIL ALLOSTERY AND DIRECT BINDING TO

ACTIVATE INTEGRINS Article Open access 12 December 2023 MECHANISM OF INTEGRIN ACTIVATION BY TALIN AND ITS COOPERATION WITH KINDLIN Article Open access 29 April 2022 MIRNA-200C-3P TARGETS

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496–510 (2007). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank H. Marttila, J. Siivonen, L. Lahtinen, R. Kaukonen, E. Väänänen, K. Silva and A. Arola for

technical assistance. P.R. Elliot is acknowledged for the recombinant talin 1–400 protein. R. Fässler, M. Ginsberg, J. Norman and S. Lee are acknowledged for the plasmids. This study has

been supported by the Academy of Finland, EU-FP06 project ENLIGHT, a European Research Council Starting Grant, the Sigrid Juselius Foundation, the European Molecular Biology Organization

(EMBO) Young Investigator Programme and Finnish Cancer Organizations. J.P. and E.M., Academy of Finland postdoc grant; T.P., Turku Graduate School of Biomedical Sciences; S.V., Alexander von

Humbold foundation and an EMBO long-term fellowship. C.S.P. and J.P.S were supported by the National Institutes of Health (T32 DK07449-28 to C.S.P. and AR49288 to J.P.S.). AUTHOR

INFORMATION Author notes * Juha K. Rantala and Jeroen Pouwels: These authors contributed equally to this work AUTHORS AND AFFILIATIONS * Medical Biotechnology, VTT Technical Research Centre

of Finland, 20521 Turku, Finland Juha K. Rantala, Jeroen Pouwels, Teijo Pellinen, Stefan Veltel, Petra Laasola, Elina Mattila, Olli Kallioniemi & Johanna Ivaska * Centre for

Biotechnology, University of Turku, 20520 Turku, Finland Jeroen Pouwels, Teijo Pellinen, Stefan Veltel, Elina Mattila & Johanna Ivaska * The Jackson Laboratory, Bar Harbor, Maine 04609,

USA Christopher S. Potter, Ted Duffy & John P. Sundberg * Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, University of Helsinki, 00014 University of Helsinki, Helsinki,

Finland Olli Kallioniemi * Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK Janet A. Askari & Martin J.

Humphries * Randall Division of Cell and Molecular Biophysics, King’s College London Guy’s Campus, London SE1 1UL, UK Maddy Parsons * MediCity Research Laboratory and Department of Medical

Biochemistry and Genetics, University of Turku, and National Institute for Health and Welfare, FIN-20520 Turku, Finland Marko Salmi * Department of Biochemistry and Food Chemistry,

University of Turku, 20520 Turku, Finland Johanna Ivaska Authors * Juha K. Rantala View author publications You can also search for this author inPubMed Google Scholar * Jeroen Pouwels View

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Veltel View author publications You can also search for this author inPubMed Google Scholar * Petra Laasola View author publications You can also search for this author inPubMed Google

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search for this author inPubMed Google Scholar * Olli Kallioniemi View author publications You can also search for this author inPubMed Google Scholar * Janet A. Askari View author

publications You can also search for this author inPubMed Google Scholar * Martin J. Humphries View author publications You can also search for this author inPubMed Google Scholar * Maddy

Parsons View author publications You can also search for this author inPubMed Google Scholar * Marko Salmi View author publications You can also search for this author inPubMed Google

Scholar * Johanna Ivaska View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS J.K.R. and O.K. developed cell spot microarrays, J.K.R. and T.P.

carried out the screen. J.K.R., J.P., P.L., S.V. and J.I. carried out the experiments. E.M. immortalized the MEFs. M.P. carried out the FRET-FLIM, C.S.P, T.D. and J.P.S. contributed to the

mouse data, J.A.A. and M.J.H. contributed to the legs together integrin experiments and M.S. contributed to the leukocyte work. J.P., J.I. and M.S. wrote the manuscript. CORRESPONDING AUTHOR

Correspondence to Johanna Ivaska. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Rantala, J., Pouwels, J., Pellinen, T. _et al._ SHARPIN is an endogenous inhibitor of β1-integrin activation. _Nat Cell Biol_ 13,

1315–1324 (2011). https://doi.org/10.1038/ncb2340 Download citation * Received: 18 May 2011 * Accepted: 09 August 2011 * Published: 25 September 2011 * Issue Date: November 2011 * DOI:

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