Control of integrin activity is vital during development and tissue homeostasis, while derailment of integrin function contributes to pathophysiological processes. Phosphorylation of a conserved threonine motif (T788/T789) in the integrin β cytoplasmic domain increases integrin activity. Here, we report that T788/T789 functions as a phospho-switch, which determines the association with either talin and kindlin-2, the major integrin activators, or filaminA, an integrin activity suppressor. A genetic screen identifies the phosphatase PPM1F as the critical enzyme, which selectively and directly dephosphorylates the T788/T789 motif. PPM1F-deficient cell lines show constitutive integrin phosphorylation, exaggerated talin binding, increased integrin activity, and enhanced cell adhesion. These gain-of-function phenotypes are reverted by reexpression of active PPM1F, but not a phosphatase-dead mutant. Disruption of the ppm1f gene in mice results in early embryonic death at day E10.5. Together, PPM1F controls the T788/T789 phospho-switch in the integrin β1 cytoplasmic tail and constitutes a novel target to modulate integrin activity.
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7 December 2020
Article|
October 29 2020
PPM1F controls integrin activity via a conserved phospho-switch
Tanja M. Grimm,
1
Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, Konstanz, Germany
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
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Nina I. Dierdorf,
1
Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, Konstanz, Germany
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
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Karin Betz,
Karin Betz
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
3
Lehrstuhl Zelluläre Chemie, Fachbereich Chemie, Universität Konstanz, Konstanz, Germany
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Christoph Paone,
Christoph Paone
1
Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, Konstanz, Germany
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
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Christof R. Hauck
1
Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, Konstanz, Germany
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
Correspondence to Christof R. Hauck: christof.hauck@uni-konstanz.de
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Tanja M. Grimm
1
Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, Konstanz, Germany
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
Nina I. Dierdorf
1
Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, Konstanz, Germany
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
Karin Betz
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
3
Lehrstuhl Zelluläre Chemie, Fachbereich Chemie, Universität Konstanz, Konstanz, Germany
Christoph Paone
1
Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, Konstanz, Germany
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
Christof R. Hauck
1
Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, Konstanz, Germany
2
Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany
Correspondence to Christof R. Hauck: christof.hauck@uni-konstanz.de
*
T.M. Grimm and N.I. Dierdorf contributed equally to this paper.
Received:
January 09 2020
Revision Received:
July 20 2020
Accepted:
September 11 2020
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
Deutsche Forschungsgemeinschaft
(CRC969 project B06)
© 2020 Grimm et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2020) 219 (12): e202001057.
Article history
Received:
January 09 2020
Revision Received:
July 20 2020
Accepted:
September 11 2020
Citation
Tanja M. Grimm, Nina I. Dierdorf, Karin Betz, Christoph Paone, Christof R. Hauck; PPM1F controls integrin activity via a conserved phospho-switch. J Cell Biol 7 December 2020; 219 (12): e202001057. doi: https://doi.org/10.1083/jcb.202001057
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