Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P42574 (
caspase-3
)
45,978
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Inhibitory PAS domain protein
(
IPAS
) is a bifunctional protein that downregulates hypoxic gene expression and exerts proapoptotic activity by preventing prosurvival activity of Bcl-x
L
and its related factors. Proapoptotic activity of
IPAS
is attenuated by the activation of the PINK1-Parkin pathway, and involved in neuronal degeneration in an experimental mouse model of Parkinson's disease. The current study shows that phosphorylation of
IPAS
at Ser184 by MAPK-activated protein kinase 2 (MK2 or MAPKAPK2) enhances the proapoptotic function of
IPAS
. Perinuclear clustering of mitochondria and activation of
caspase-3
caused by the transient expression of EGFP-
IPAS
were increased by UVB irradiation. The C-terminal region of
IPAS
mediated the UVB susceptibility of
IPAS
. Increase in
IPAS
-induced mitochondrial clustering by UVB was completly inhibited by the p38 MAPK inhibitor SB203580. Mass spectrometry analysis of UVB-activated
IPAS
identified several phosphorylation sites in the C-terminal region containing p38 MAPK consensus phosphorylation sites at Ser219 and Ser223, and an MK2 consensus site at Ser184. Although mutations of Ser219 and Ser223 to Ala did not suppress the UVB-induced mitochondrial clustering, replacement of Ser184 with Ala blocked it. A phosphomimetic substitution at Ser184 enhanced mitochondrial clustering and activation of
caspase-3
without UVB exposure. Furthermore, binding affinity to Bcl-x
L
was increased by the mutation. Treatment of PC12 cells with CoCl
2
caused activation of MK2 and mitochondrial clustering.
IPAS
-dependent cell death induced by CoCl
2
in PC12 cells was decreased by the treatment with the MK2 inhibitor MK2 inhibitor III and by siRNA-directed silencing of MK2.
...
PMID:Increase in proapoptotic activity of inhibitory PAS domain protein via phosphorylation by MK2. 2905 8
