Dlg5 Regulates Dendritic Spine Formation and Synaptogenesis by Controlling Subcellular N-Cadherin Localization

Wang, Shih Hsiu J.; Celic, Ivana; Choi, Se‐Young; Riccomagno, Martin M.; Wang, Qiang; Sun, Lu; Mitchell, Sarah; Vasioukhin, Valeri; Huganir, Richard L.; Kolodkin, Alex L.

doi:10.1523/jneurosci.1280-14.2014

Cited by 35 publications

(30 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Looking at the Adherens junction, we found that E-Cad level was not affected (n=18) (Fig 6A). Follicle cells also expressed N-Cad, which is integrated in adherens junction, and Dlg5 has been functionally and molecularly linked to this cadherin in mammals [10,12,25]. We therefore looked at N-Cad and spotted an extremely strong and fully penetrant reduction in Dlg5 mutant cells (n>20) (Fig 6B).…”

Section: Dlg5 Is Required For N-cadherin Localization Independently Omentioning

confidence: 99%

Multiple functions of the scaffold protein Discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster

Venugopal¹,

Veyssière²,

Couderc³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background : Scaffold proteins support a variety of key processes during animal development. Mutant mouse for the MAGUK protein Discs large 5 (Dlg5) presents a general growth impairment and moderate morphogenetic defects. Results : Here, we generated null mutants for Drosophila Dlg5 and show that it owns similar functions in growth and epithelial architecture. Dlg5 is required for growth at a cell autonomous level in several tissues and at the organism level, affecting cell size and proliferation. Our results are consistent with Dlg5 modulating hippo pathway in the wing disc, including the impact on cell size, a defect that is reproduced by the loss of yorkie. However, other observations indicate that Dlg5 regulates growth by at least another way that may involve Myc protein but nor PI3K neither TOR pathways. Moreover, epithelia cells mutant for Dlg5 also show a reduction of apical domain determinants, though not sufficient to induce a complete loss of cell polarity. Dlg5 is also essential, in the same cells, for the presence at Adherens junctions of N-Cadherin, but not E-Cadherin. Genetic analyses indicate that junction and polarity defects are independent. Conclusions : Together our data show that Dlg5 own several conserved functions that are independent of each other in regulating growth, cell polarity and cell adhesion. Moreover, they reveal a differential regulation of E-cadherin and N-cadherin apical localization.

show abstract

Section: Dlg5 Is Required For N-cadherin Localization Independently Omentioning

confidence: 99%

Multiple functions of the scaffold protein Discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster

Venugopal¹,

Veyssière²,

Couderc³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…CARMA3 has been implicated in facilitating GPCR-induced activation of NFkB via lysophosphatidic acid, endothelin-1, and angiotensin II (Scudiero et al, 2014). Although there does not appear to be any examples of DLG5 in the direct regulation of GPCRs, DLG5 has been implicated in regulating synaptogenesis by enhancing the membrane localization of the transmembrane protein N-cadherin (Wang et al, 2014). DLG5 has also been demonstrated to scaffold atypical protein kinase C (PKC) isoforms, and this provides a mechanism by which DLG5 contributes to the regulation of GPCR-mediated signaling (Nechiporuk et al, 2013).…”

Section: Gpcr-interacting Psd-95 Family Pdz Domain-mentioning

confidence: 99%

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Dunn

Ferguson

2015

Molecular Pharmacology

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins, postsynaptic density protein of 95 kilodaltons, disc large, zona occludens-1 (PDZ) domain-containing proteins appear most abundant and have similarly been implicated in disease mechanisms. PDZ proteins play an important role in regulating receptor and channel protein localization within synapses and tight junctions and function to scaffold intracellular signaling protein complexes. In the current study, we review the known functional interactions between PDZ domain-containing proteins and GPCRs and provide insight into the potential mechanisms of action. These PDZ domain-containing proteins include the membraneassociated guanylate-like kinases [postsynaptic density protein of 95 kilodaltons; synapse-associated protein of 97 kilodaltons; postsynaptic density protein of 93 kilodaltons; synapse-associated protein of 102 kilodaltons; discs, large homolog 5; caspase activation and recruitment domain and membrane-associated guanylate-like kinase domain-containing protein 3; membrane protein, palmitoylated 3; calcium/calmodulin-dependent serine protein kinase; membrane-associated guanylate kinase protein (MAGI)-1, MAGI-2, and MAGI-3], Na 1 /H 1 exchanger regulatory factor proteins (NHERFs) (NHERF1, NHERF2, PDZ domaincontaining kidney protein 1, and PDZ domain-containing kidney protein 2), Golgi-associated PDZ proteins (Ga-binding protein interacting protein, C-terminus and CFTR-associated ligand), PDZ domain-containing guanine nucleotide exchange factors (GEFs) 1 and 2, regulator of G protein signaling (RGS)-homology-RhoGEFs (PDZ domain-containing RhoGEF and leukemia-associated RhoGEF), RGS3 and RGS12, spinophilin and neurabin-1, SRC homology 3 domain and multiple ankyrin repeat domain (Shank) proteins (Shank1, Shank2, and Shank3), partitioning defective proteins 3 and 6, multiple PDZ protein 1, Tamalin, neuronal nitric oxide synthase, syntrophins, protein interacting with protein kinase C a 1, syntenin-1, and sorting nexin 27.

show abstract

“…We showed previously that Dlg5 −/− mice display prominent defects in apical-basal cell polarity and develop brain hydrocephalus, synaptogenesis defects, emphysema-like lungs, and kidney cysts (Nechiporuk et al 2007(Nechiporuk et al , 2013Wang et al 2014). Dlg5 is necessary for the proper maintenance and proliferation of progenitor cells in vivo, and Dlg5 −/− pups and adult mice are correspondingly much smaller than their wild-type littermates.…”

mentioning

confidence: 98%

DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

et al. 2016

View full text Add to dashboard Cite

Disruption of apical-basal polarity is implicated in developmental disorders and cancer; however, the mechanisms connecting cell polarity proteins with intracellular signaling pathways are largely unknown. We determined previously that membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) functions in cell polarity and regulates cellular proliferation and differentiation via undefined mechanisms. We report here that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, which controls organ size through the modulation of cell proliferation and differentiation. Affinity purification/mass spectrometry revealed a critical role of DLG5 in the formation of protein assemblies containing core Hippo kinases mammalian ste20 homologs 1/2 (MST1/2) and Par-1 polarity proteins microtubule affinity-regulating kinases 1/2/3 (MARK1/2/3). Consistent with this finding, Hippo signaling is markedly hyperactive in mammalian Dlg5 −/− tissues and cells in vivo and ex vivo and in Drosophila upon dlg5 knockdown. Conditional deletion of Mst1/2 fully rescued the phenotypes of brain-specific Dlg5 knockout mice. Dlg5 also interacts genetically with Hippo effectors Yap1/Taz. Mechanistically, we show that DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity. These data reveal a direct connection between cell polarity proteins and Hippo, which is essential for proper development of multicellular organisms.

show abstract

Dlg5 Regulates Dendritic Spine Formation and Synaptogenesis by Controlling Subcellular N-Cadherin Localization

Cited by 35 publications

References 57 publications

Multiple functions of the scaffold protein Discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster

Multiple functions of the scaffold protein Discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

Contact Info

Product

Resources

About