Phagocytosis of Apoptotic Cells Is Regulated by a UNC-73/TRIO-MIG-2/RhoG Signaling Module and Armadillo Repeats of CED-12/ELMO

deBakker, Colin; Haney, Lisa B.; Kinchen, Jason M.; Grimsley, Cynthia; Lu, Mingjian; Klingele, Doris; Hsu, Pei Ken; Chou, Bin Kuan; Cheng, Li; Blangy, Anne; Sondek, John; Hengartner, Michael O.; Wu, Yi-Chun; Ravichandran, Kodi S.

doi:10.1016/j.cub.2004.12.029

Cited by 188 publications

(159 citation statements)

References 41 publications

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“…19,20 To address whether CED-2 : CED-5 interaction is required for cell migration, we assayed migration of the gonadal distal tip cells (DTCs), which define the shape of the adult hermaphrodite gonad. 12 Interestingly, expression of CED-5(1-1715) in CED-5-deficient worms was able to rescue DTC migration as efficiently as the wild-type CED-5 (Table 1b). These data suggested that the direct interaction of CED-2 and CED-5 is not required for efficient engulfment or DTC migration in C. elegans.…”

Section: Resultsmentioning

confidence: 94%

“…The small GTPase RhoG has recently been suggested to mediate ELMO : Dock180 complex recruitment to the membrane, in turn potentially regulating Rac activation during engulfment. 12,13 We next asked whether RhoG might serve as a link between the CrkII and the Dock180 : ELMO submodules. When we coexpressed a dominant-negative form of RhoG (RhoG T17N ) with CrkII, it was able to partially inhibit CrkII-mediated phagocytosis ( Figure 6, compare bars 8-2).…”

Section: Resultsmentioning

confidence: 99%

“…10,11 Two additional players, MIG-2/RHOG and UNC-73/Trio, play a role upstream of ELMO : Dock180. 12,13 The binding of ELMO to activated GTP-bound RhoG may serve as one mechanism for recruitment of the ELMO : Dock180 complex to the membrane, leading to Rac activation.…”

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confidence: 99%

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Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells

Kinchen

Brugnera

et al. 2007

Cell Death Differ

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Removal of apoptotic cells is a dynamic process coordinated by ligands on apoptotic cells, and receptors and other signaling proteins on the phagocyte. One of the fundamental challenges is to understand how different phagocyte proteins form specific and functional complexes to orchestrate the recognition/removal of apoptotic cells. One evolutionarily conserved pathway involves the proteins cell death abnormal (CED)-2/chicken tumor virus no. 10 (CT10) regulator of kinase (Crk)II, CED-5/180 kDa protein downstream of chicken tumor virus no. 10 (Crk) (Dock180), CED-12/engulfment and migration (ELMO) and MIG-2/RhoG, leading to activation of the small GTPase CED-10/Rac and cytoskeletal remodeling to promote corpse uptake. Although the role of ELMO : Dock180 in regulating Rac activation has been well defined, the function of CED-2/CrkII in this complex is less well understood. Here, using functional studies in cell lines, we observe that a direct interaction between CrkII and Dock180 is not required for efficient removal of apoptotic cells. Similarly, mutants of CED-5 lacking the CED-2 interaction motifs could rescue engulfment and migration defects in CED-5 deficient worms. Mutants of CrkII and Dock180 that could not biochemically interact could colocalize in membrane ruffles. Finally, we identify MIG-2/RhoG (which functions upstream of Dock180 : ELMO) as a possible point of crosstalk between these two signaling modules. Taken together, these data suggest that Dock180/ELMO and CrkII act as two evolutionarily conserved signaling submodules that coordinately regulate engulfment. Apoptotic cells are generated by diverse physiological processes, ranging from the elimination of damaged (or precancerous) cells to deletion of cells during developmental morphogenesis; 1,2 the culmination of the apoptotic program is the phagocytosis (or engulfment) of the apoptotic cell. In mammals, prompt removal of apoptotic cells is required to prevent the release of potential self-antigens and onset of autoimmune-like syndromes. [3][4][5] Removal of the apoptotic cell can be divided into several mechanistic steps: first, dying cells expose 'eat-me' signals, which are recognized by receptors on phagocytic cells. 6 These signals, both positive (such as phosphatidylserine and MFG-E8) 2 and negative (such as CD31 and CD47), are rapidly modified following the onset of apoptosis, facilitating removal of the apoptotic cell. A number of receptors have been identified that either directly or indirectly facilitate apoptotic cell recognition; however, signaling following corpse recognition is less well characterized.Recognition of the apoptotic cell by the phagocyte leads to the formation of an actin-rich phagocytic cup, followed by the internalization of the target. 7 Genetic studies in the nematode Caenorhabditis elegans (C. elegans) have led to the identification of eight genes that play a partially redundant role in removal of apoptotic cells. 2 Of these, cell death abnormal (CED)-2/chicken tumor virus no. 10 (CT10) regulator of kinase (Crk)II, C...

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells

Kinchen

Brugnera

et al. 2007

Cell Death Differ

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“…Four different signaling pathways act upstream of this heterotrimeric CED‐5/Dock180, CED‐12/Elmo, CED‐2/Crk‐II GEF complex to activate it in the cell (Fig. 4B): (B.1) One goes through the GEF UNC‐73/Trio, which activates the small GTPase MIG‐2 /RhoG and hence regulates the CED‐5/Dock180‐CED‐12/Elmo GEF complex 65 and recruits it to the membrane.(B.2) Wnt pathway components, between the frizzled receptor and APR1/APC, act genetically upstream of CED‐10/Rac during cell corpse engulfment. In C. elegans , stimulation of the Wnt pathway leads to activation of the glycogen synthase kinase GSK‐3, which acts in a complex with APR‐1/APC.…”

Section: Ced‐10/rac Is At the Core Of The Phagocytosis Of Apoptotic Cmentioning

confidence: 99%

“…(B.1) One goes through the GEF UNC‐73/Trio, which activates the small GTPase MIG‐2 /RhoG and hence regulates the CED‐5/Dock180‐CED‐12/Elmo GEF complex 65 and recruits it to the membrane.…”

Section: Ced‐10/rac Is At the Core Of The Phagocytosis Of Apoptotic Cmentioning

confidence: 99%

Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated

et al. 2016

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Small GTPases in the Rho family act as major nodes with functions beyond cytoskeletal rearrangements shaping the Caenorhabditis elegans embryo during development. These small GTPases are key signal transducers that integrate diverse developmental signals to produce a coordinated response in the cell. In C. elegans, the best studied members of these highly conserved Rho family small GTPases, RHO‐1/RhoA, CED‐10/Rac, and CDC‐42, are crucial in several cellular processes dealing with cytoskeletal reorganization. In this review, we update the functions described for the Rho family small GTPases in spindle orientation and cell division, engulfment, and cellular movements during C. elegans embryogenesis, focusing on the Rho subfamily Rac.Please also see the video abstract here

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Transglutaminase 2 Dysfunctions in the Development of Autoimmune Disorders: Celiac Disease and TG2 ⁻ ^/ ⁻ Mouse

Szondy

Korponay-Szabó

Király

et al. 2011

Advances in Enzymology - And Related Areas of Molecular Biology

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Phagocytosis of Apoptotic Cells Is Regulated by a UNC-73/TRIO-MIG-2/RhoG Signaling Module and Armadillo Repeats of CED-12/ELMO

Cited by 188 publications

References 41 publications

Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells

Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells

Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated

Transglutaminase 2 Dysfunctions in the Development of Autoimmune Disorders: Celiac Disease and TG2 ⁻ ^/ ⁻ Mouse

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Phagocytosis of Apoptotic Cells Is Regulated by a UNC-73/TRIO-MIG-2/RhoG Signaling Module and Armadillo Repeats of CED-12/ELMO

Cited by 188 publications

References 41 publications

Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells

Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells

Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated

Transglutaminase 2 Dysfunctions in the Development of Autoimmune Disorders: Celiac Disease and TG2 − / − Mouse

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Transglutaminase 2 Dysfunctions in the Development of Autoimmune Disorders: Celiac Disease and TG2 ⁻ ^/ ⁻ Mouse