Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex

Brugnera, Enrico; Haney, Lisa; Grimsley, Cynthia; Lu, Mingjian; Walk, Scott F.; Tosello-Trampont, Annie-Carole; Macara, Ian G.; Madhani, Hiten; Fink, Gerald R.; Ravichandran, Kodimangalam S.

doi:10.1038/ncb824

Cited by 576Protein Kinase Regulation and GTPase SignalingCellular transport and secretionCellular Mechanics and Interactions

Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex

Brugnera, Enrico, Haney, Lisa, Grimsley, Cynthia, Lu, Mingjian, Walk, Scott F., Tosello-Trampont, Annie-Carole, Macara, Ian G., Madhani, Hiten +2 more·2002·Nature Cell Biology

DOI 10.1038/ncb824

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Abstract

Mammalian Dock180 and ELMO proteins, and their homologues in Caenorhabditis elegans and Drosophila melanogaster, function as critical upstream regulators of Rac during development and cell migration. The mechanism by which Dock180 or ELMO mediates Rac activation is not understood. Here, we identify a domain within Dock180 (denoted Docker) that specifically recognizes nucleotide-free Rac and can mediate GTP loading of Rac in vitro. The Docker domain is conserved among known Dock180 family members in metazoans and in a yeast protein. In cells, binding of Dock180 to Rac alone is insufficient for GTP loading, and a Dock180 ELMO1 interaction is required. We can also detect a trimeric ELMO1 Dock180 Rac1 complex and ELMO augments the interaction between Dock180 and Rac. We propose that the Dock180 ELMO complex functions as an unconventional two-part exchange factor for Rac.

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Authors: Brugnera, E., Haney, L., Grimsley, C., Lu, M., Walk, S. F., Tosello-Trampont, A.-C., Macara, I. G., Madhani, H., Fink, G. R., & Ravichandran, K. S.
Affiliations: University of Virginia (US)
University of California, San Francisco (US)
Whitehead Institute for Biomedical Research (US)
ORCID: Lu, Mingjian
Macara, Ian G.
Madhani, Hiten
Fink, Gerald R.
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2002-07-15
Volume: 4
Issue: 8
Pages: 574-582
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/ncb824
OpenAlex: W2069986934
Cited by: 576
References: 33
Citations by year: 2026: 5 · 2025: 7 · 2024: 16 · 2023: 16 · 2022: 21 · 2021: 19 · 2020: 9 · 2019: 21 · 2018: 17 · 2017: 18 · 2016: 24 · 2015: 16 · 2014: 25 · 2013: 32 · 2012: 33
FWCI: 12.75
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
Funders: American Cancer Society
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 transport and secretion
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords: DOCK180, ELMo, Rac GTPase, GTP loading, Rac1, cell migration, Rho GTPase signaling
MeSH terms: Amino Acid Sequence, Animals, Binding Sites, Carrier Proteins, Cell Line, Cytoskeletal Proteins, Guanosine Triphosphate, Humans, Molecular Sequence Data, Phagocytosis, Proteins, Recombinant Proteins, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Guanine Nucleotide Exchange Factors, rac GTP-Binding Proteins, Caenorhabditis elegans Proteins, Macromolecular Substances, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins

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Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex

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