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; Madeline Parsons; Marko Salmi; Johanna Ivaska

doi:10.1038/ncb2340

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, Madeline Parsons, Marko Salmi, Johanna Ivaska

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164 Citations (Scopus)

Abstract

Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate beta 1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of beta 1-integrins in an RNAi screen. SHARPIN inhibited beta 1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased beta 1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin alpha-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of beta 1-integrins from inactive to active conformations.

Original language	English
Pages (from-to)	1315–1324
Number of pages	17
Journal	Nature Cell Biology
Volume	13
Issue number	11
Early online date	25 Sept 2011
DOIs	https://doi.org/10.1038/ncb2340
Publication status	Published - Nov 2011

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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 beta 1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of beta 1-integrins in an RNAi screen. SHARPIN inhibited beta 1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased beta 1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin alpha-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of beta 1-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 Madeline Parsons and Marko Salmi and Johanna Ivaska",

year = "2011",

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doi = "10.1038/ncb2340",

language = "English",

volume = "13",

pages = "1315–1324",

journal = "Nature Cell Biology",

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

AU - Rantala, Juha K.

AU - Pouwels, Jeroen

AU - Pellinen, Teijo

AU - Veltel, Stefan

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, Madeline

AU - Salmi, Marko

AU - Ivaska, Johanna

PY - 2011/11

Y1 - 2011/11

N2 - Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate beta 1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of beta 1-integrins in an RNAi screen. SHARPIN inhibited beta 1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased beta 1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin alpha-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of beta 1-integrins from inactive to active conformations.

AB - Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate beta 1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of beta 1-integrins in an RNAi screen. SHARPIN inhibited beta 1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased beta 1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin alpha-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of beta 1-integrins from inactive to active conformations.

U2 - 10.1038/ncb2340

DO - 10.1038/ncb2340

M3 - Article

SN - 1465-7392

VL - 13

SP - 1315

EP - 1324

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 11

ER -

SHARPIN is an endogenous inhibitor of β1-integrin activation

Abstract

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