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Cited by 20Cell Adhesion Molecules ResearchCellular Mechanics and InteractionsBiochemical and Structural Characterization

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Sharpin suppresses β1-integrin activation by complexing with the β1 tail and kindlin-1

Open access
Gao, Juan, Bao, Yun, Ge, Shushu, Sun, Peisen, Sun, Jiaojiao, Liu, Jianmin, Chen, Feng, Han, Li, Cao, Zhongyuan, Qin, Jun, White, Gilbert C., Xu, Zhen, Ma, Yan-Qing·2019·Cell Communication and Signaling
DOI 10.1186/s12964-019-0407-6PMC PMC6700787
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Abstract

BACKGROUND: Previously sharpin has been identified as an endogenous inhibitor of β1-integrin activation by directly binding to a conserved region in the cytoplasmic tails (CTs) of the integrin β1-associated α subunits. METHODS: Here we employed biochemical approaches and cellular analyses to evaluate the function and molecular mechanism of the sharpin-kindlin-1 complex in regulating β1-integrin activation. RESULTS: In this study, we found that although the inhibition of sharpin on β1-integrin activation could be confirmed, sharpin had no apparent effect on integrin αIIbβ3 activation in CHO cell system. Notably, a direct interaction between sharpin and the integrin β1 CT was detected, while the interaction of sharpin with the integrin αIIb and the β3 CTs were substantially weaker. Importantly, sharpin was able to inhibit the talin head domain binding to the integrin β1 CT, which can mechanistically contribute to inhibiting β1-integrin activation. Interestingly, we also found that sharpin interacted with kindlin-1, and the interaction between sharpin and the integrin β1 CT was significantly enhanced when kindlin-1 was present. Consistently, we observed that instead of acting as an activator, kindlin-1 actually suppressed the talin head domain mediated β1-integrin activation, indicating that kindlin-1 may facilitate recruitment of sharpin to the integrin β1 CT. CONCLUSION: Taken together, our findings suggest that sharpin may complex with both kindlin-1 and the integrin β1 CT to restrict the talin head domain binding, thus inhibiting β1-integrin activation.

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  • 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 Gao, Bao et al., 2019

    The Background (page not specified) says SHARPIN participates in multiple cellular signaling pathways and describes its roles in LUBAC and integrin regulation. The Discussion (page not specified) describes SHARPIN binding intracellular integrin tails and kindlin-1, but our copy does not establish that it is mainly cytoplasmic or explicitly characterize it as an adaptor protein. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Metadata

Authors
Gao, J., Bao, Y., Ge, S., Sun, P., Sun, J., Liu, J., Chen, F., Han, L., Cao, Z., Qin, J., White, G. C., Xu, Z., & Ma, Y.-Q.
Affiliations
  • Shanghai University (CN)
  • Cleveland Clinic (US)
  • Medical College of Wisconsin (US)
Corresponding author
  • Xu, Zhen
  • Ma, Yan-Qing
ORCID
Venue
Cell Communication and Signaling
Publisher
Springer Science and Business Media LLC
Published
2019-08-20
Volume
17
Issue
1
Pages
101-101
ISSN
1478-811X (ISSN-L)
DOI
10.1186/s12964-019-0407-6
PMC
PMC6700787
OpenAlex
W2969368622
Cited by
20
References
2
Citations by year
2025: 3 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 3
FWCI
2.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Communication and Signaling (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • NIH (HL131654)
  • NNSFC (31500618, 31571177, 31770967)
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
Keywords
SHARPIN, β1 integrin activation, kindlin-1, integrin cytoplasmic tail, integrin αIIbβ3, protein complex formation, integrin-mediated adhesion
MeSH terms
Animals, Carrier Proteins, Cricetulus, Signal Transduction, CHO Cells, 3T3 Cells, Integrin beta1, Intracellular Signaling Peptides and Proteins, Mice

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