Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex

R. S. D'Souza; J. Y. Lim; A. Turgut; K. Servage; J. Zhang; K. Orth; N. G. Sosale; M. J. Lazzara; J. C. Allegood; J. E. Casanova

doi:10.1101/866392

Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex

R. S. D'Souza, J. Y. Lim, A. Turgut, K. Servage, J. Zhang, K. Orth, N. G. Sosale, M. J. Lazzara, J. C. Allegood, J. E. Casanova

Research output: Contribution to journal › Article › peer-review

Abstract

Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca²⁺ influx, however our understanding of this process remains incomplete. Here we show that Ca²⁺ influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca²⁺-activated GEF IQSec1, and that both IQSec1 and Arf5 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid transfer protein ORP3, and that Ca²⁺ influx triggers PKC-dependent translocation of this complex to ER/plasma membrane contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell migration.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/866392
State	Published - Dec 5 2019

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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@article{8a25cefcaa1a48098a2bf92594855d16,

title = "Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex",

abstract = "Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca2+ influx, however our understanding of this process remains incomplete. Here we show that Ca2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca2+-activated GEF IQSec1, and that both IQSec1 and Arf5 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid transfer protein ORP3, and that Ca2+ influx triggers PKC-dependent translocation of this complex to ER/plasma membrane contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell migration.",

author = "D'Souza, {R. S.} and Lim, {J. Y.} and A. Turgut and K. Servage and J. Zhang and K. Orth and Sosale, {N. G.} and Lazzara, {M. J.} and Allegood, {J. C.} and Casanova, {J. E.}",

note = "Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2019",

month = dec,

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doi = "10.1101/866392",

language = "English (US)",

journal = "Seminars in Fetal and Neonatal Medicine",

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AU - D'Souza, R. S.

AU - Lim, J. Y.

AU - Turgut, A.

AU - Servage, K.

AU - Zhang, J.

AU - Orth, K.

AU - Sosale, N. G.

AU - Lazzara, M. J.

AU - Allegood, J. C.

AU - Casanova, J. E.

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2019/12/5

Y1 - 2019/12/5

N2 - Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca2+ influx, however our understanding of this process remains incomplete. Here we show that Ca2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca2+-activated GEF IQSec1, and that both IQSec1 and Arf5 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid transfer protein ORP3, and that Ca2+ influx triggers PKC-dependent translocation of this complex to ER/plasma membrane contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell migration.

AB - Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca2+ influx, however our understanding of this process remains incomplete. Here we show that Ca2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca2+-activated GEF IQSec1, and that both IQSec1 and Arf5 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid transfer protein ORP3, and that Ca2+ influx triggers PKC-dependent translocation of this complex to ER/plasma membrane contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell migration.

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