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Cited by 7Cell Adhesion Molecules ResearchProtein Kinase Regulation and GTPase SignalingCellular Mechanics and Interactions

Lfc subcellular localization and activity is controlled by αv-class integrin

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Coló, Georgina P., Seiwert, Andrea, Haga, Raquel B.·2023·Journal of Cell Science
DOI 10.1242/jcs.260740
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Abstract

Fibronectin (FN)-binding integrins control a variety of cellular responses through Rho GTPases. The FN-binding integrins, αvβ3 and α5β1, are known to induce different effects on cell morphology and motility. Here, we report that FN-bound αvβ3 integrin, but not FN-bound α5β1 integrin, triggers the dissociation of the RhoA GEF Lfc (also known as GEF-H1 and ARHGEF2 in humans) from microtubules (MTs), leading to the activation of RhoA, formation of stress fibres and maturation of focal adhesions (FAs). Conversely, loss of Lfc expression decreases RhoA activity, stress fibre formation and FA size, suggesting that Lfc is the major GEF downstream of FN-bound αvβ3 that controls RhoA activity. Mechanistically, FN-engaged αvβ3 integrin activates a kinase cascade involving MARK2 and MARK3, which in turn leads to phosphorylation of several phospho-sites on Lfc. In particular, S151 was identified as the main site involved in the regulation of Lfc localization and activity. Our findings indicate that activation of Lfc and RhoA is orchestrated in FN-adherent cells in an integrin-specific manner.

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  • Phosphorylation of GEFH1 by PAR-1/MARK at sites within the C1-DH linker near the C1 domain releases GEFH1 from microtubules.

    “Phosphorylation of GEFH1 by partitioning-defective 1/microtubule affinity-regulating kinase (PAR-1/MARK) at sites within the C1-DH linker near the C1 domain releases GEFH1 from microtubules24”

    From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [48]

    The section “MARK2 and MARK3 kinases are involved in Lfc release from MTs” states that PAR-1/MARK kinases phosphorylate Lfc/GEF-H1 and that phosphorylation at S151 leads to its release from microtubules. The copy does not locate the relevant sites within a C1–DH linker near the C1 domain, so that structural detail is unsupported. No page numbers are available in the indexed passages. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Coló, G. P., Seiwert, A., & Haga, R. B.
Affiliations
Max Planck Institute of Biochemistry (DE)
Corresponding author
Seiwert, Andrea
ORCID
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2023-05-01
Volume
136
Issue
9
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
DOI
10.1242/jcs.260740
OpenAlex
W4367668407
Cited by
7
References
2
Citations by year
2026: 1 · 2025: 4 · 2024: 2
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
www.biologists.com/user-licence-1-1/ (vor)
Locations
  • Journal of Cell Science (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Bundesministerium für Bildung und Forschung
  • Ministerio de Ciencia, Tecnología e Innovación Productiva
  • Agencia Nacional de Promoción Científica y Tecnológica
  • Max Planck Society
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
GEF-H1, ARHGEF2, RhoA, integrin αvβ3, alpha5beta1 integrin, fibronectin, focal adhesion maturation, microtubule binding, MARK2, MARK3, protein phosphorylation, integrin signaling, cell adhesion
MeSH terms
Humans, Phosphorylation, Integrins, Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, Integrin alpha5beta1, Integrin alphaV, Rho Guanine Nucleotide Exchange Factors

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