PH domain of ELMO functions in trans to regulate Rac activation via Dock180

Lu, Mingjian; Kinchen, Jason M.; Rossman, Kent L.; Grimsley, Cynthia; deBakker, Colin; Brugnera, Enrico; Tosello-Trampont, Annie; Haney, Lisa B.; Klingele, Doris; Sondek, John; Hengartner, Michael O.; Ravichandran, Kodi S.

doi:10.1038/nsmb800

Cited by 125 publications

(125 citation statements)

References 31 publications

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“…In the first pathway, the proteins CED-2, CED-5 and CED-12 (mammalian homologues CrkII, Dock180 and ELMO, respectively) function to activate CED-10 (Rac) and worms deficient in any of these protein can be rescued by overexpression of Ced-10. 49 In the second group, the candidate receptor CED-1 (CD91/LRP) probably recognises an unknown ligand on the apoptotic cell and signals via its cytoplasmic tail to the adaptor protein CED-6 (hCED-6/ GULP), whereas CED-7 (ABCA?) is thought to play a role in membrane dynamics.…”

Section: Engulfmentmentioning

confidence: 99%

Clearance of apoptotic cells by phagocytes

2007

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Phagocytic clearance of apoptotic cells may be considered to consist of four distinct steps: accumulation of phagocytes at the site where apoptotic cells are located; recognition of dying cells through a number of bridge molecules and receptors; engulfment by a unique uptake process; and processing of engulfed cells within phagocytes. Here, we will discuss these individual steps that collectively are essential for the effective removal of apoptotic cells. This will illustrate our relative lack of knowledge about the initial attraction signals, the specific mechanisms of engulfment and processing in comparison to the extensive literature on recognition mechanisms. There is now mounting evidence that clearance defects are responsible for chronic inflammatory disease and contribute to autoimmunity. Therefore, a better understanding of all aspects of the clearance process is required before it can truly be manipulated for therapeutic gain.

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Section: Engulfmentmentioning

confidence: 99%

Clearance of apoptotic cells by phagocytes

2007

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“…To provide insight into the molecular context in which Dictyostelium Dock180-related proteins function, we isolated the DockD complex and uncovered DdELMO1, a Dictyostelium ELMO protein. Among the five ELMO domain-containing proteins that are encoded by the Dictyostelium genome, DdELMO1 is the only one that contains the proline-rich region at the C-terminus that mediates Dock180-ELMO interaction (Supplemental Figure S2; Lu et al, 2004). According to the steric-inhibition model proposed by Lu et al, at the basal state, the N-terminal SH3 domain of Dock180 binds to the distant CZH2 domain and negatively regulates the function of the protein as it prevents the interaction with Rac.…”

Section: Dockd Forms a Complex With Dictyostelium Elmo1 And Rac Gtpasesmentioning

confidence: 99%

DictyosteliumDock180-related RacGEFs Regulate the Actin Cytoskeleton during Cell Motility

Para

Krischke

Merlot

et al. 2009

MBoC

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Cell motility of amoeboid cells is mediated by localized F-actin polymerization that drives the extension of membrane protrusions to promote forward movements. We show that deletion of either of two members of the Dictyostelium Dock180 family of RacGEFs, DockA and DockD, causes decreased speed of chemotaxing cells. The phenotype is enhanced in the double mutant and expression of DockA or DockD complements the reduced speed of randomly moving DockD null cells' phenotype, suggesting that DockA and DockD are likely to act redundantly and to have similar functions in regulating cell movement. In this regard, we find that overexpressing DockD causes increased cell speed by enhancing F-actin polymerization at the sites of pseudopod extension. DockD localizes to the cell cortex upon chemoattractant stimulation and at the leading edge of migrating cells and this localization is dependent on PI3K activity, suggesting that DockD might be part of the pathway that links PtdIns(3,4,5)P 3 production to F-actin polymerization. Using a proteomic approach, we found that DdELMO1 is associated with DockD and that Rac1A and RacC are possible in vivo DockD substrates. In conclusion, our work provides a further understanding of how cell motility is controlled and provides evidence that the molecular mechanism underlying Dock180-related protein function is evolutionarily conserved. INTRODUCTIONIn eukaryotes, cell migration is essential for many biological processes such as embryonic development and tissue renewal and in humans it is also linked to numerous pathologies including cancer. Cells are set in motion through reorganization of the actin cytoskeleton that creates cytoplasmic protrusions and promotes forward movement. Members of the Rac subfamily of Rho small GTPases are key regulators of cytoskeletal dynamics in virtually all eukaryotes. Activated Rac proteins relay directional signals from the leading edge of migrating cells to downstream effectors such as SCAR/WAVE and WASP proteins that mediate F-actin polymerization and power cell motility (Jaffe and Hall, 2005;Ridley, 2006;Charest and Firtel, 2007;Kolsch et al., 2008;Ladwein and Rottner, 2008). Despite their importance, the upstream signaling mechanisms that mediate Rac activation during cell migration are still unclear.The activity of the small GTPases is regulated through a GDP/GTP exchange mechanism that is catalyzed by the guanine nucleotide exchange factors (GEF), GTPase-activating proteins (GAPs), and guanine nucleotide-dissociation inhibitors (GDIs). GEFs activate GTPases by catalyzing the dissociation of GDP from the protein, thereby allowing the binding of GTP and their switch to an active state. Members of the classical Dbl homology-pleckstrin homology (DH-PH) domain-containing family were thought to be the universal activators of Rho GTPases until the CZH (CDM-zizimin homology) family of unconventional Rho-GEFs was discovered (Côté and Vuori, 2002;Meller et al., 2005;Côté and Vuori, 2007). In the CZH proteins, a CZH2 domain, rather than a DH domain, interacts wi...

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“…The amino-terminal 558 amino-acid residues (N-term) were necessary for targeting of the ELMO-Dock180 complex to the membrane 14,17 , whereas the carboxy-terminal 196 residues (C-term) were necessary for binding Dock180 and for optimal Rac activation 15,16 . Because the receptor(s) upstream of ELMO1 during engulfment were not known, we performed a yeast two-hybrid screen, with N-term as bait.…”

mentioning

confidence: 99%

“…Previous studies revealed two 'functional' regions within ELMO1 and its Caenorhabditis elegans homologue CED-12 during phagocytosis 5,[14][15][16][17] . The amino-terminal 558 amino-acid residues (N-term) were necessary for targeting of the ELMO-Dock180 complex to the membrane 14,17 , whereas the carboxy-terminal 196 residues (C-term) were necessary for binding Dock180 and for optimal Rac activation 15,16 .…”

mentioning

confidence: 99%

BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module

Park

Tosello‐Trampont

Elliott

et al. 2007

Nature

Self Cite

738

741

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Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms [1][2][3] . ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses 4,5 ; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment [4][5][6] . However, the receptor(s) upstream of the ELMO/ Dock180/Rac module are still unknown. Here we identify brainspecific angiogenesis inhibitor 1 (BAI1) as a receptor upstream of ELMO and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a seven-transmembrane protein belonging to the adhesion-type G-protein-coupled receptor family, with an extended extracellular region 7-9 and no known ligands. We show that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, we identify phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells 10-13 , as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, decreased BAI1 expression or interference with BAI1 function inhibits the engulfment of apoptotic targets ex vivo and in vivo. Thus, BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells.Previous studies revealed two 'functional' regions within ELMO1 and its Caenorhabditis elegans homologue CED-12 during phagocytosis 5,14-17 . The amino-terminal 558 amino-acid residues (N-term) were necessary for targeting of the ELMO-Dock180 complex to the membrane 14,17 , whereas the carboxy-terminal 196 residues (C-term) were necessary for binding Dock180 and for optimal Rac activation 15,16 . Because the receptor(s) upstream of ELMO1 during engulfment were not known, we performed a yeast two-hybrid screen, with N-term as bait. After screening more than 1.1 3 10 7 colonies from a mouse embryo library, followed by several subscreens for specificity, we identified a single membrane protein, BAI1.BAI1 belongs to subgroup VII of the adhesion-type G-proteincoupled receptor (GPCR) family 7-9 , with extended extracellular termini containing multiple domains and motifs that are thought to function in cell-cell or cell-matrix interactions 9 . BAI1 (1,584 residues) has an 943-residue extracellular region, a seven-transmembrane

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PH domain of ELMO functions in trans to regulate Rac activation via Dock180

Cited by 125 publications

References 31 publications

Clearance of apoptotic cells by phagocytes

Clearance of apoptotic cells by phagocytes

DictyosteliumDock180-related RacGEFs Regulate the Actin Cytoskeleton during Cell Motility

BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module

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