In Silico Screening for Palmitoyl Substrates Reveals a Role for DHHC1/3/10 (zDHHC1/3/11)-mediated Neurochondrin Palmitoylation in Its Targeting to Rab5-positive Endosomes

Oku, Shinichiro; Takahashi, Naoki; Fukata, Yuko; Fukata, Masaki

doi:10.1074/jbc.m112.431676

Cited by 42 publications

(46 citation statements)

References 54 publications

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“…Many of these have reported roles in the endocytic pathway, including AP-3, myosin VI, VPS35, Dnajc6, dynamin 1-like, dynamin 3, Rab21, SNAP91, and neurochondrin (42)(43)(44)(45)(46). We further show that HA-NL2 can undergo dynamin-dependent endocytosis in neurons, triggered by incubation with the soluble ectodomain of neurexin 1␤, and that endocytosed HA-NL2 is present in VPS35 retromer-containing organelles.…”

Section: Discussionmentioning

confidence: 70%

“…Regulated Endocytosis of NL2-A striking aspect of the list of putative HFY-NL2-associated proteins is the number of components involved in membrane protein trafficking (Table 1). Among these, many have reported roles in the endocytic pathway, including AP-3, myosin VI, VPS35, Dnajc6, dynamin 1-like, dynamin 3, Rab21, SNAP91, and neurochondrin (42)(43)(44)(45)(46). As an initial functional test of whether NL2 undergoes dynamin-dependent regulated endocytosis, we expressed NL2 with an extracellular HA tag in cultured hippocampal neurons, labeled surface HA-NL2 with FITC-conjugated rat anti-HA Fab fragment, and followed the fate of this labeled NL2 upon application of soluble ligand.…”

Section: Table 1 Proteins Associated With Hfy-nl2mentioning

confidence: 99%

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A Combined Transgenic Proteomic Analysis and Regulated Trafficking of Neuroligin-2

Kang

Cassidy

et al. 2014

Journal of Biological Chemistry

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Background: Brain inhibitory synaptic connections present challenges for molecular identification and imaging. Results: Transgenic mice expressing tagged neuroligin-2 were used to identify associated complexes and image inhibitory synapses in multiple brain regions. Conclusion: Neuroligin-2-associated complexes are enriched in synaptic components, and neuroligin-2 undergoes regulated dynamin-dependent endocytosis and retromer association. Significance: New data and approaches are presented for brain inhibitory synapse proteomics and imaging.

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Section: Discussionmentioning

confidence: 70%

Section: Table 1 Proteins Associated With Hfy-nl2mentioning

confidence: 99%

A Combined Transgenic Proteomic Analysis and Regulated Trafficking of Neuroligin-2

Kang

Cassidy

et al. 2014

Journal of Biological Chemistry

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“…Four such modifications are known for intracellular proteins: palmitoylation, myristoylation, farnesylation, and geranylgeranylation, of which palmitoylation is most frequently observed for neuronal proteins (16,17). Palmitoylation is best known to target proteins to the plasma membrane, but can also target proteins to vesicles (18)(19)(20). However, roles for palmitoylation in axonal retrograde trafficking and signaling have not been described.…”

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confidence: 99%

Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling

Holland

Collura

Ketschek

et al. 2015

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

103

231

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Dual leucine-zipper kinase (DLK) is critical for axon-to-soma retrograde signaling following nerve injury. However, it is unknown how DLK, a predicted soluble kinase, conveys long-distance signals and why homologous kinases cannot compensate for loss of DLK. Here, we report that DLK, but not homologous kinases, is palmitoylated at a conserved site adjacent to its kinase domain. Using short-hairpin RNA knockdown/rescue, we find that palmitoylation is critical for DLK-dependent retrograde signaling in sensory axons. This functional importance is because of three novel cellular and molecular roles of palmitoylation, which targets DLK to trafficking vesicles, is required to assemble DLK signaling complexes and, unexpectedly, is essential for DLK's kinase activity. By simultaneously controlling DLK localization, interactions, and activity, palmitoylation ensures that only vesiclebound DLK is active in neurons. These findings explain how DLK specifically mediates nerve injury responses and reveal a novel cellular mechanism that ensures the specificity of neuronal kinase signaling.

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“…3ϫ HA and EGFP tags were at the N terminus of the ZDHHC3 protein, and the His tag was located at the C terminus of the FGFR1 protein. An NCAM180⌬ construct, in which the four cysteine residues located in the intracellular domain adjacent to transmembrane domain were replaced by serines, and an HA-ZDHHC3/ C157S construct abolishing the catalytic activity of the enzyme were described previously (19,34,36,37). A plasmid encoding the ␥2 subunit of the GABA receptor was kindly provided by Andrea Barberis.…”

mentioning

confidence: 99%

ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation

Lievens

Kuznetsova

Kochlamazashvili

et al. 2016

Molecular and Cellular Biology

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The neural cell adhesion molecule (NCAM) mediates cell-cell and cell-matrix adhesion. It is broadly expressed in the nervous system and regulates neurite outgrowth, synaptogenesis, and synaptic plasticity. Previous in vitro studies revealed that palmitoylation of NCAM is required for fibroblast growth factor 2 (FGF2)-stimulated neurite outgrowth and identified the zinc finger DHHC (Asp-His-His-Cys)-containing proteins ZDHHC3 and ZDHHC7 as specific NCAM-palmitoylating enzymes. Here, we verified that FGF2 controlled NCAM palmitoylation in vivo and investigated molecular mechanisms regulating NCAM palmitoylation by ZDHHC3. Experiments with overexpression and pharmacological inhibition of FGF receptor (FGFR) and Src revealed that these kinases control tyrosine phosphorylation of ZDHHC3 and that ZDHHC3 is phosphorylated by endogenously expressed FGFR and Src proteins. By site-directed mutagenesis, we found that Tyr18 is an FGFR1-specific ZDHHC3 phosphorylation site, while Tyr295 and Tyr297 are specifically phosphorylated by Src kinase in cell-based and cell-free assays. Abrogation of tyrosine phosphorylation increased ZDHHC3 autopalmitoylation, enhanced interaction with NCAM, and upregulated NCAM palmitoylation. Expression of ZDHHC3 with tyrosine mutated in cultured hippocampal neurons promoted neurite outgrowth. Our findings for the first time highlight that FGFR-and Src-mediated tyrosine phosphorylation of ZDHHC3 modulates ZD-HHC3 enzymatic activity and plays a role in neuronal morphogenesis.

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In Silico Screening for Palmitoyl Substrates Reveals a Role for DHHC1/3/10 (zDHHC1/3/11)-mediated Neurochondrin Palmitoylation in Its Targeting to Rab5-positive Endosomes

Cited by 42 publications

References 54 publications

A Combined Transgenic Proteomic Analysis and Regulated Trafficking of Neuroligin-2

A Combined Transgenic Proteomic Analysis and Regulated Trafficking of Neuroligin-2

Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling

ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation

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