Journal Article

DZNE-2020-05050

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation.

Lievens, P. M. ; Kuznetsova, T. ; Kochlamazashvili, G. ; Cesca, F. ; Gorinski, N. ; Galil, D. A. ; Cherkas, V. ; Ronkina, N. ; Lafera, J. ; Gaestel, M. ; Ponimaskin, E. (Corresponding author) ; Dityatev, A. (Last author)DZNE*

2016
Soc. Washington, DC

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Please use a persistent id in citations: doi:10.1128/MCB.00144-16

Abstract: 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 ZDHHC3 enzymatic activity and plays a role in neuronal morphogenesis.

Keyword(s): Acyltransferases: genetics (MeSH) ; Acyltransferases: metabolism (MeSH) ; Animals (MeSH) ; Cells, Cultured (MeSH) ; Fibroblast Growth Factor 2: metabolism (MeSH) ; Gene Expression Regulation (MeSH) ; Lipoylation (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Mice (MeSH) ; Mutation (MeSH) ; Neural Cell Adhesion Molecules: metabolism (MeSH) ; Neurites: metabolism (MeSH) ; Phosphorylation (MeSH) ; Receptors, Fibroblast Growth Factor: metabolism (MeSH) ; Tyrosine: genetics (MeSH) ; Tyrosine: metabolism (MeSH) ; src-Family Kinases: metabolism (MeSH) ; GODZ protein, mouse ; Membrane Proteins ; Neural Cell Adhesion Molecules ; Receptors, Fibroblast Growth Factor ; Fibroblast Growth Factor 2 ; Tyrosine ; Acyltransferases ; src-Family Kinases

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Contributing Institute(s):

1. Molecular Neuroplasticity (AG Dityatev)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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