Rac GTPase-activating protein (Rac GAP) α1-Chimaerin undergoes proteasomal degradation and is stabilized by diacylglycerol signaling in neurons.
α1-Chimaerin is a neuron-specific member of the Rho GTPase-activating protein family that selectively inactivates the small GTPase Rac. It is known to regulate the structure of dendrites and dendritic spines. We describe here that under basal conditions α1-chimaerin becomes polyubiquitinated and undergoes rapid proteasomal degradation. This degradation is partly dependent on the N-terminal region that is unique to this isoform. Mimicking diacylglycerol (DAG) signaling with a phorbol ester stabilizes endogenous α1-chimaerin against degradation and causes accumulation of the protein. The stabilization requires phorbol ester binding via the C1 domain of the protein and is independent of PKC activity. In addition, overexpression of a constitutively active Rac1 mutant is sufficient to cause an accumulation of α1-chimaerin through a phospholipase C-dependent mechanism, showing that endogenous DAG signaling can also stabilize the protein. These results suggest that signaling via DAG may regulate the abundance of α1-chimaerin under physiological conditions, providing a new model for understanding how its activity could be controlled.
Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
Jamie R K
JR
Marland
DingXin
D
Pan
Philip C
PC
Buttery
D000595:Amino Acid Sequence; D000818:Animals; D020848:Chimerin 1 / Q000737:chemistry* / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D020848:Chimerin 1; D004075:Diglycerides; D020033:Protein Isoforms; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D020830:rac1 GTP-Binding Protein; D013755:Tetradecanoylphorbol Acetate