The Cdc42 Guanine Nucleotide Exchange Factor FGD6 Coordinates Cell Polarity and Endosomal Membrane Recycling in Osteoclasts

Steenblock, Charlotte; Heckel, Tobias; Czupalla, Cornelia; Santo, Ana Isabel Espírito; Niehage, Christian; Sztacho, Martin; Hoflack, Bernard

doi:10.1074/jbc.m113.504894

Cited by 57 publications

(46 citation statements)

References 46 publications

(49 reference statements)

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“…Although not proposed in the published work, these studies suggest that Cdc42, Par6, and aPKC are likely to be required for retrograde recycling in Drosophila, as we have proposed here in C. elegans. In addition, work in fission yeast and polarized mammalian cells also suggests a requirement for Cdc42 in endocytic recycling (38,59,60). Thus, CDC-42 and associated protein function in retrograde recycling likely have an ancient origin and a widely conserved function.…”

Section: Discussionmentioning

confidence: 99%

A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

Bai

Grant

2015

Proc. Natl. Acad. Sci. U.S.A.

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Endosome-to-Golgi transport is required for the function of many key membrane proteins and lipids, including signaling receptors, small-molecule transporters, and adhesion proteins. The retromer complex is well-known for its role in cargo sorting and vesicle budding from early endosomes, in most cases leading to cargo fusion with the trans-Golgi network (TGN). Transport from recycling endosomes to the TGN has also been reported, but much less is understood about the molecules that mediate this transport step. Here we provide evidence that the F-BAR domain proteins TOCA-1 and TOCA-2 (Transducer of Cdc42 dependent actin assembly), the small GTPase CDC-42 (Cell division control protein 42), associated polarity proteins PAR-6 (Partitioning defective 6) and PKC-3/atypical protein kinase C, and the WAVE actin nucleation complex mediate the transport of MIG-14/Wls and TGN-38/TGN38 cargo proteins from the recycling endosome to the TGN in Caenorhabditis elegans. Our results indicate that CDC-42, the TOCA proteins, and the WAVE component WVE-1 are enriched on RME-1-positive recycling endosomes in the intestine, unlike retromer components that act on early endosomes. Furthermore, we find that retrograde cargo TGN-38 is trapped in early endosomes after depletion of SNX-3 (a retromer component) but is mainly trapped in recycling endosomes after depletion of CDC-42, indicating that the CDC-42-associated complex functions after retromer in a distinct organelle. Thus, we identify a group of interacting proteins that mediate retrograde recycling, and link these proteins to a poorly understood trafficking step, recycling endosome-to-Golgi transport. We also provide evidence for the physiological importance of this pathway in WNT signaling.retromer | endocytic recycling | endosome | toca | wave

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Section: Discussionmentioning

confidence: 99%

A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

Bai

Grant

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…There is some evidence that the C. elegans ortholog of Cdc42 plays a role in EC tubulogenesis. First, either loss or excessive activity of EXC-5, an ortholog of the faciogenital dysplasia-associated (FGD) family of guanine exchange factors (GEFs) that specifically activate Cdc42 in biochemical and cell culture assays (Hayakawa et al, 2008;Huber et al, 2008;Kurogane et al, 2012;Miyamoto et al, 2003;Steenblock et al, 2014;Umikawa et al, 1999;Zheng et al, 1996), causes defects in EC tubulogenesis (Buechner et al, 1999;Gao et al, 2001;Mattingly and Buechner, 2011;Suzuki et al, 2001). Second, reduced cdc-42 activity causes mild EC phenotypes associated with defects in endocytic trafficking (Lant et al, 2015), and overexpression of wild-type, dominant-negative, or activated CDC-42 also affect EC tubulogenesis (Mattingly and Buechner, 2011).…”

Section: Introductionmentioning

confidence: 99%

A network of conserved formins, regulated by the guanine exchange factor EXC-5 and the GTPase CDC-42, modulates tubulogenesis in vivo

Shaye

Greenwald

2016

Development

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The C. elegans excretory cell (EC) is a powerful model for tubulogenesis, a conserved process that requires precise cytoskeletal regulation. EXC-6, an ortholog of the diseaseassociated formin INF2, coordinates cell outgrowth and lumen formation during EC tubulogenesis by regulating F-actin at the tip of the growing canal and the dynamics of basolateral microtubules. EXC-6 functions in parallel with EXC-5/FGD, a predicted activator of the Rho GTPase Cdc42. Here, we identify the parallel pathway: EXC-5 functions through CDC-42 to regulate two other formins: INFT-2, another INF2 ortholog, and CYK-1, the sole ortholog of the mammalian diaphanous (mDia) family of formins. We show that INFT-2 promotes F-actin accumulation in the EC, and that CYK-1 inhibits INFT-2 to regulate F-actin levels and EXC-6-promoted outgrowth. As INF2 and mDia physically interact and cross-regulate in cultured cells, our work indicates that a conserved EXC-5−CDC-42 pathway modulates this regulatory interaction and that it is functionally important in vivo during tubulogenesis.

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“…IQGAP1 has been found to form complexes with Cdc42, Guanine Nucleotide exchange factor FGD6, the Rho GTPase-activating protein ARHGAP10, filamin and talin close to focal adhesions [41]. Talin-PI(4,5)P 2 mediate the activation and the function of integrins [42], including the formation of talin-integrin clusters [43].…”

Section: Iqgap1 Regulates β-Actin Complex Formation In Response To Prmentioning

confidence: 99%

IQGAP1 connects phosphoinositide signaling to cytoskeletal reorganization

Yerramilli

Ross

Lindberg³

et al. 2019

Preprint

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IQGAP1 is a multi-domain protein that acts as a scaffold for multiple signaling pathways. IQGAP1 generates the lipid messenger PI(3,4,5)P 3 by scaffolding the phosphoinositide kinases PIPKIs and PI3K.The dynamics of this scaffolding protein complex in intact, living cells are unknown. Here, we delineate the role of IQGAP1 in PI(3,4,5)P 3 -mediated signaling in live cells under basal and stimulated conditions using fluorescence lifetime imaging microscopy. We demonstrate that IQGAP1 interacts strongly with PIPKIγ at intracellular entities and on the plasma membrane, and scaffolds PI3K and PIPKIγ in response to physiological changes. Additionally, we show that IQGAP1 scaffolds phosphoinositides with PI3K, PIPKIγ and EGFR, and forms clusters upon cell stimulation with epidermal growth factor. Importantly, we show that IQGAP1 connects PI(3,4,5)P 3 -mediated signaling and cytoskeletal signaling pathways by binding PIPKIγ in proximity of the cytoskeletal proteins talin and Cdc42. Our results support a model in which IQGAP1 mediates crosstalk between phosphoinositide signaling and the cytoskeleton to promote directed cell movement. IQGAP1 connects PI signaling to cytoskeletal reorganization

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The Cdc42 Guanine Nucleotide Exchange Factor FGD6 Coordinates Cell Polarity and Endosomal Membrane Recycling in Osteoclasts

Cited by 57 publications

References 46 publications

A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

A network of conserved formins, regulated by the guanine exchange factor EXC-5 and the GTPase CDC-42, modulates tubulogenesis in vivo

IQGAP1 connects phosphoinositide signaling to cytoskeletal reorganization

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