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Cited by 22Cell Adhesion Molecules ResearchNF-κB Signaling PathwaysImmune Cell Function and Interaction

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Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling

Open access
De Franceschi, Nicola, Peuhu, Emilia, Parsons, Maddy, Rissanen, Sami, Vattulainen, Ilpo, Salmi, Marko, Ivaska, Johanna, Pouwels, Jeroen·2015·PLOS ONE
DOI 10.1371/journal.pone.0143423PMC PMC4658161
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Abstract

SHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin α-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-κB) activity as a component of the linear ubiquitin chain assembly complex (LUBAC). However, it is currently unclear how regulation of these seemingly different roles is coordinated. Here, we show that SHARPIN binds integrin and LUBAC in a mutually exclusive manner. We map the integrin binding site on SHARPIN to the ubiquitin-like (UBL) domain, the same domain implicated in SHARPIN interaction with LUBAC component RNF31 (ring finger protein 31), and identify two SHARPIN residues (V267, L276) required for both integrin and RNF31 regulation. Accordingly, the integrin α-tail is capable of competing with RNF31 for SHARPIN binding in vitro. Importantly, the full SHARPIN RNF31-binding site contains residues (F263A/I272A) that are dispensable for SHARPIN-integrin interaction. Importantly, disrupting SHARPIN interaction with integrin or RNF31 abolishes SHARPIN-mediated regulation of integrin or NF-κB activity, respectively. Altogether these data suggest that the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct.

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Crossref · 10.1371/journal.pone.0143423

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  • SHARPIN regulates cell adhesion and migration either by inhibition of integrins or by promotion of lamellipodium formation through the ARP2/3 complex.

    “What is known is that SHARPIN regulates cell adhesion and migration either by inhibition of integrins”

    From SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis (2022) · cites this paper as De Franceschi et al., 2015

    The Introduction (page unavailable) describes SHARPIN as an integrin inactivator, and the Results section on SHARPIN V267A reports that integrin inhibition affects cell migration. Our copy does not support the additional claim that SHARPIN promotes lamellipodium formation through the ARP2/3 complex. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • SHARPIN is a cytoplasmic adaptor protein involved in the regulation of multiple cellular functions.

    “SHANK-associated RH domain interactor (SHARPIN) is mainly a cytoplasmic adaptor protein involved in the regulation of multiple cellular functions”

    From SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis (2022) · cites this paper as De Franceschi, Peuhu et al., 2015

    The Discussion (page not provided) describes SHARPIN as multifunctional, with likely scaffolding or adaptor-like functions. The Results show that it binds integrin cytoplasmic tails, but the paper does not establish that SHARPIN is mainly cytoplasmic; the Discussion also suggests a nuclear function. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • SHARPIN functions as a signalling coordinator.

    “Multiple cellular functions indicate that different signalling pathways compete for SHARPIN, and that SHARPIN functions as a signalling coordinator (De Franceschi et al., 2015).”

    From SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis (2022) · cites this paper as De Franceschi et al., 2015

    The Discussion describes SHARPIN as a possible signalling coordinator and suggests that pathways may compete for it. The citing sentence presents that competition more firmly than the source does; the Discussion explicitly says whether competition determines the balance between pathways is unknown. Page numbers are not provided in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Different signalling pathways compete for SHARPIN.

    “Multiple cellular functions indicate that different signalling pathways compete for SHARPIN, and that SHARPIN functions as a signalling coordinator (De Franceschi et al., 2015).”

    From SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis (2022) · cites this paper as De Franceschi et al., 2015

    The Discussion says SHARPIN’s multiple functions suggest that signaling pathways may compete for it and that it may act as a signaling coordinator. It also says whether competition determines the balance between pathways is unknown. The cited sentence presents this proposed competition more firmly than the source does. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • At least some of these roles of SHARPIN are mutually exclusive.

    “at least some of these roles of SHARPIN are mutually exclusive (De Franceschi et al., 2015).”

    From SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis (2022) · cites this paper as De Franceschi et al., 2015

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Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 30

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Metadata

Authors
De Franceschi, N., Peuhu, E., Parsons, M., Rissanen, S., Vattulainen, I., Salmi, M., Ivaska, J., & Pouwels, J.
Affiliations
  • University of Turku (FI)
  • King's College London (GB)
  • Tampere University of Technology (FI)
  • University of Southern Denmark (DK)
Corresponding author
  • Ivaska, Johanna
  • Pouwels, Jeroen
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-11-23
Volume
10
Issue
11
Pages
e0143423
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0143423
PMC
PMC4658161
OpenAlex
W2268801575
Cited by
22
References
2
Citations by year
2023: 2 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 4 · 2017: 4 · 2016: 3
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, other-oa)
  • UTUPub (University of Turku) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Yale University
  • Finnish Cancer Institute
  • University College London
  • Magnus Ehrnroothin Säätiö
  • Orionin Tutkimussäätiö
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords
SHARPIN, NF-κB signaling, LUBAC, RNF31, ubiquitin-like domain, integrin alpha subunit, linear ubiquitination, protein-protein interaction, integrin binding site
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Cell Line, Cell Movement, Humans, Models, Biological, Molecular Sequence Data, Nerve Tissue Proteins, Protein Binding, Signal Transduction, Integrins, NF-kappa B, Protein Structure, Tertiary, Protein Interaction Mapping, Ubiquitin-Protein Ligases, Mutant Proteins, Mice

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