TY  - JOUR
AU  - Lievens, Patricia Marie-Jeanne
AU  - Kuznetsova, Tatiana
AU  - Kochlamazashvili, Gaga
AU  - Cesca, Fabrizia
AU  - Gorinski, Natalya
AU  - Galil, Dalia Abdel
AU  - Cherkas, Volodimir
AU  - Ronkina, Natalia
AU  - Lafera, Juri
AU  - Gaestel, Matthias
AU  - Ponimaskin, Evgeni
AU  - Dityatev, Alexander
TI  - ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation.
JO  - Molecular and cellular biology
VL  - 36
IS  - 17
SN  - 0270-7306
CY  - Washington, DC
PB  - Soc.
M1  - DZNE-2020-05050
SP  - 2208-2225
PY  - 2016
AB  - 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.
KW  - Acyltransferases: genetics
KW  - Acyltransferases: metabolism
KW  - Animals
KW  - Cells, Cultured
KW  - Fibroblast Growth Factor 2: metabolism
KW  - Gene Expression Regulation
KW  - Lipoylation
KW  - Membrane Proteins: genetics
KW  - Membrane Proteins: metabolism
KW  - Mice
KW  - Mutation
KW  - Neural Cell Adhesion Molecules: metabolism
KW  - Neurites: metabolism
KW  - Phosphorylation
KW  - Receptors, Fibroblast Growth Factor: metabolism
KW  - Tyrosine: genetics
KW  - Tyrosine: metabolism
KW  - src-Family Kinases: metabolism
KW  - GODZ protein, mouse (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Neural Cell Adhesion Molecules (NLM Chemicals)
KW  - Receptors, Fibroblast Growth Factor (NLM Chemicals)
KW  - Fibroblast Growth Factor 2 (NLM Chemicals)
KW  - Tyrosine (NLM Chemicals)
KW  - Acyltransferases (NLM Chemicals)
KW  - src-Family Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27247265
C2  - pmc:PMC4985929
DO  - DOI:10.1128/MCB.00144-16
UR  - https://pub.dzne.de/record/138728
ER  -