TY  - JOUR
AU  - Wirth, Alexander
AU  - Chen-Wacker, Chen
AU  - Wu, Yao-Wen
AU  - Gorinski, Nataliya
AU  - Filippov, Mikhail A
AU  - Pandey, Ghanshyam
AU  - Ponimaskin, Evgeni
TI  - Dual lipidation of the brain-specific Cdc42 isoform regulates its functional properties.
JO  - Biochemical journal
VL  - 456
IS  - 3
SN  - 0264-6021
CY  - London
PB  - Portland Press67261
M1  - DZNE-2020-03508
SP  - 311-322
PY  - 2013
AB  - Cdc42 (cell division cycle 42) is a member of the Rho GTPase family which regulates a variety of cellular activities by controlling actin cytoskeleton and gene expression. Cdc42 is expressed in the form of two splice variants. The canonical Cdc42 isoform is prenylated (Cdc42-prenyl), whereas the brainspecific isoform can be palmitoylated (Cdc42-palm). In the present study we have demonstrated palmitoylation of endogenous Cdc42 in rodent and human brains and identified Cys(188) and Cys(189) as acylation sites of Cdc42-palm. Moreover, we have shown that Cys(188) can also be prenylated. Analysis of acylation-deficient mutants revealed that lipidation of Cys(188) is essential for proper membrane binding of Cdc42-palm as well as for Cdc42-mediated regulation of gene transcription and induction of densely packed filopodia in neuroblastoma cells. We also found that Cdc42-prenyl is a dominant splice variant in a wide range of commonly used cell lines as well as in the cerebellum, whereas Cdc42-palm is the main Cdc42 isoform in hippocampus, where it is critically involved in the formation of dendritic filopodia and spines. Replacement of endogenous Cdc42 by its acylation-deficient mutants revealed the importance of Cdc42-palm lipidation for its morphogenic and synaptogenic effects in neurons. These findings demonstrate that dual lipidation of Cdc42-palm represents an important regulator of morphogenic signalling in hippocampal neurons.
KW  - Animals
KW  - Cell Line, Tumor
KW  - Cerebellum: cytology
KW  - Cerebellum: metabolism
KW  - Cysteine: genetics
KW  - Cysteine: metabolism
KW  - Dendrites: genetics
KW  - Dendrites: metabolism
KW  - Hippocampus: cytology
KW  - Hippocampus: metabolism
KW  - Humans
KW  - Isoenzymes: genetics
KW  - Isoenzymes: metabolism
KW  - Lipoylation: physiology
KW  - Mice
KW  - Organ Specificity: physiology
KW  - Protein Prenylation: physiology
KW  - Pseudopodia: genetics
KW  - Pseudopodia: metabolism
KW  - Transcription, Genetic: physiology
KW  - cdc42 GTP-Binding Protein: genetics
KW  - cdc42 GTP-Binding Protein: metabolism
KW  - Cdc42 protein, mouse (NLM Chemicals)
KW  - Isoenzymes (NLM Chemicals)
KW  - cdc42 GTP-Binding Protein (NLM Chemicals)
KW  - Cysteine (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24059268
DO  - DOI:10.1042/BJ20130788
UR  - https://pub.dzne.de/record/137186
ER  -