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

114 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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Integrins
Talin
Leukocytes
RNA Interference
Keratinocytes
Cell Adhesion
Cell Movement
Homeostasis
Fibroblasts
Neoplasms

Cite this

Rantala, J. K., Pouwels, J., Pellinen, T., Veltel, S., Laasola, P., Mattila, E., ... Ivaska, J. (2011). SHARPIN is an endogenous inhibitor of β1-integrin activation. Nature Cell Biology, 13, 1315-1324. https://doi.org/10.1038/ncb2340
Rantala, Juha K. ; Pouwels, Jeroen ; Pellinen, Teijo ; Veltel, Stefan ; Laasola, Petra ; Mattila, Elina ; Potter, Christopher S. ; Duffy, Ted ; Sundberg, John P. ; Kallioniemi, Olli ; Askari, Janet A. ; Humphries, Martin J. ; Parsons, Maddy ; Salmi, Marko ; Ivaska, Johanna. / SHARPIN is an endogenous inhibitor of β1-integrin activation. In: Nature Cell Biology. 2011 ; Vol. 13. pp. 1315-1324.
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title = "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.",
author = "Rantala, {Juha K.} and Jeroen Pouwels and Teijo Pellinen and Stefan Veltel and Petra Laasola and Elina Mattila and Potter, {Christopher S.} and Ted Duffy and Sundberg, {John P.} and Olli Kallioniemi and Askari, {Janet A.} and Humphries, {Martin J.} and Maddy Parsons and Marko Salmi and Johanna Ivaska",
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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 2011, 'SHARPIN is an endogenous inhibitor of β1-integrin activation', Nature Cell Biology, vol. 13, pp. 1315-1324. https://doi.org/10.1038/ncb2340

SHARPIN is an endogenous inhibitor of β1-integrin activation. / Rantala, Juha K.; Pouwels, Jeroen; Pellinen, Teijo; Veltel, Stefan; Laasola, Petra; Mattila, Elina; Potter, Christopher S.; Duffy, Ted; Sundberg, John P.; Kallioniemi, Olli; Askari, Janet A.; Humphries, Martin J.; Parsons, Maddy; Salmi, Marko; Ivaska, Johanna (Corresponding Author).

In: Nature Cell Biology, Vol. 13, 2011, p. 1315-1324.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - SHARPIN is an endogenous inhibitor of β1-integrin activation

AU - Rantala, Juha K.

AU - Pouwels, Jeroen

AU - Pellinen, Teijo

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AU - Laasola, Petra

AU - Mattila, Elina

AU - Potter, Christopher S.

AU - Duffy, Ted

AU - Sundberg, John P.

AU - Kallioniemi, Olli

AU - Askari, Janet A.

AU - Humphries, Martin J.

AU - Parsons, Maddy

AU - Salmi, Marko

AU - Ivaska, Johanna

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AB - 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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Rantala JK, Pouwels J, Pellinen T, Veltel S, Laasola P, Mattila E et al. SHARPIN is an endogenous inhibitor of β1-integrin activation. Nature Cell Biology. 2011;13:1315-1324. https://doi.org/10.1038/ncb2340