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

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

doi:10.1038/ncb824

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

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

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478 Scopus citations

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.

Original language	English
Pages (from-to)	574-582
Number of pages	9
Journal	Nature Cell Biology
Volume	4
Issue number	8
DOIs	https://doi.org/10.1038/ncb824
State	Published - Aug 2002

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@article{4c903769721642839652a697a8c8e353,

title = "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex",

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.",

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

note = "Funding Information: ACKNOWLEDGEMENTS We thank J. Casanova, T. Parsons and U. Lorenz for critically reading the manuscript and members of the Ravichandran laboratory for helpful suggestions and comments. We thank C. Der and T. Karnoub for generously providing us with the RacW56F mutant. This work was supported in part by an American Cancer Society grant to K.S.R. Correspondence and requests for material should be addressed to K.S.R. Supplementary Information is available on Nature Cell Biology{\textquoteright}s website (http://cellbio.nature.com).",

year = "2002",

month = aug,

doi = "10.1038/ncb824",

language = "English",

volume = "4",

pages = "574--582",

journal = "Nature Cell Biology",

issn = "1465-7392",

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T1 - Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex

AU - Brugnera, Enrico

AU - Haney, Lisa

AU - Grimsley, Cynthia

AU - Lu, Mingjian

AU - Walk, Scott F.

AU - Tosello-Trampont, Annie Carole

AU - Macara, Ian G.

AU - Madhani, Hiten

AU - Fink, Gerald R.

AU - Ravichandran, Kodimangalam S.

N1 - Funding Information: ACKNOWLEDGEMENTS We thank J. Casanova, T. Parsons and U. Lorenz for critically reading the manuscript and members of the Ravichandran laboratory for helpful suggestions and comments. We thank C. Der and T. Karnoub for generously providing us with the RacW56F mutant. This work was supported in part by an American Cancer Society grant to K.S.R. Correspondence and requests for material should be addressed to K.S.R. Supplementary Information is available on Nature Cell Biology’s website (http://cellbio.nature.com).

PY - 2002/8

Y1 - 2002/8

N2 - 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.

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

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