Cited by 148Protein Kinase Regulation and GTPase SignalingCellular Mechanics and InteractionsCellular transport and secretion

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Guanine Nucleotide Exchange Factor-H1 Regulates Cell Migration via Localized Activation of RhoA at the Leading Edge

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Nalbant, Perihan, Chang, Yuan-Chen, Birkenfeld, Jörg, Chang, Zee-Fen, Bokoch, Gary M.·2009·Molecular Biology of the Cell

DOI 10.1091/mbc.e09-01-0041PMC PMC2743625

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Abstract

Cell migration involves the cooperative reorganization of the actin and microtubule cytoskeletons, as well as the turnover of cell–substrate adhesions, under the control of Rho family GTPases. RhoA is activated at the leading edge of motile cells by unknown mechanisms to control actin stress fiber assembly, contractility, and focal adhesion dynamics. The microtubule-associated guanine nucleotide exchange factor (GEF)-H1 activates RhoA when released from microtubules to initiate a RhoA/Rho kinase/myosin light chain signaling pathway that regulates cellular contractility. However, the contributions of activated GEF-H1 to coordination of cytoskeletal dynamics during cell migration are unknown. We show that small interfering RNA-induced GEF-H1 depletion leads to decreased HeLa cell directional migration due to the loss of the Rho exchange activity of GEF-H1. Analysis of RhoA activity by using a live cell biosensor revealed that GEF-H1 controls localized activation of RhoA at the leading edge. The loss of GEF-H1 is associated with altered leading edge actin dynamics, as well as increased focal adhesion lifetimes. Tyrosine phosphorylation of focal adhesion kinase and paxillin at residues critical for the regulation of focal adhesion dynamics was diminished in the absence of GEF-H1/RhoA signaling. This study establishes GEF-H1 as a critical organizer of key structural and signaling components of cell migration through the localized regulation of RhoA activity at the cell leading edge.

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Authors: Nalbant, P., Chang, Y.-C., Birkenfeld, J., Chang, Z.-F., & Bokoch, G. M.
Affiliations: Scripps Research Institute (US)
National Taiwan University (TW)
ORCID: Nalbant, Perihan
Birkenfeld, Jörg
Chang, Zee-Fen
Venue: Molecular Biology of the Cell
Publisher: American Society for Cell Biology (ASCB)
Published: 2009-09-15
Volume: 20
Issue: 18
Pages: 4070-4082
ISSN: 1059-1524 (ISSN-L)
1939-4586
DOI: 10.1091/mbc.e09-01-0041
PMC: PMC2743625
OpenAlex: W2151712953
Cited by: 148
References: 60
Citations by year: 2026: 6 · 2025: 10 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 18 · 2020: 4 · 2019: 9 · 2018: 3 · 2017: 11 · 2016: 8 · 2015: 7 · 2014: 16 · 2013: 13 · 2012: 16
FWCI: 4.43
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular Biology of the Cell (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of General Medical Sciences (GM39434, R01GM039434)
Topics: 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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords: GEF-H1, RhoA, cell migration, leading edge, RhoA activation, focal adhesions, actin dynamics, focal adhesion kinase, paxillin, Rho kinase, myosin light chain, microtubules, directional migration, HeLa cells, cytoskeletal remodeling
MeSH terms: Formins, Actins, Cell Movement, Enzyme Activation, HeLa Cells, Humans, Microtubules, Pseudopodia, Signal Transduction, Phosphotyrosine, Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, Focal Adhesions, Adaptor Proteins, Signal Transducing, Rho Guanine Nucleotide Exchange Factors

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Guanine Nucleotide Exchange Factor-H1 Regulates Cell Migration via Localized Activation of RhoA at the Leading Edge

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