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Phospho-FOXO3 (Ser253)

Full Name
Phospho-FOXO3 (Ser253)
Function
Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106, PubMed:21329882, PubMed:30513302).

Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity).

Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106).

Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882).

In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301).

In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity).

Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3 (PubMed:30513302).
Biological Process
Aging Source: Ensembl
Antral ovarian follicle growth Source: Ensembl
Brain morphogenesis Source: Ensembl
Cellular response to amyloid-beta Source: Ensembl
Cellular response to corticosterone stimulus Source: Ensembl
Cellular response to glucose starvation Source: UniProtKB
Cellular response to glucose stimulus Source: Ensembl
Cellular response to hypoxia Source: Ensembl
Cellular response to nerve growth factor stimulus Source: Ensembl
Cellular response to oxidative stress Source: UniProtKB
DNA damage response, signal transduction by p53 class mediator Source: Ensembl
Extrinsic apoptotic signaling pathway in absence of ligand Source: Ensembl
Initiation of primordial ovarian follicle growth Source: Ensembl
Mitochondrial transcription Source: UniProtKB
Negative regulation of canonical Wnt signaling pathway Source: Ensembl
Negative regulation of cell migration Source: BHF-UCL
Negative regulation of neuron differentiation Source: Ensembl
Negative regulation of transcription by RNA polymerase II Source: BHF-UCL
Neuronal stem cell population maintenance Source: Ensembl
Oocyte maturation Source: Ensembl
Ovulation from ovarian follicle Source: Ensembl
Positive regulation of apoptotic process Source: BHF-UCL
Positive regulation of autophagy Source: UniProtKB
Positive regulation of endothelial cell apoptotic process Source: Ensembl
Positive regulation of erythrocyte differentiation Source: MGI
Positive regulation of hydrogen peroxide-mediated programmed cell death Source: Ensembl
Positive regulation of muscle atrophy Source: UniProtKB
Positive regulation of neuron apoptotic process Source: UniProtKB
Positive regulation of pri-miRNA transcription by RNA polymerase II Source: BHF-UCL
Positive regulation of reactive oxygen species biosynthetic process Source: Ensembl
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Regulation of neural precursor cell proliferation Source: Ensembl
Regulation of transcription by RNA polymerase II Source: UniProtKB
Regulation of translation Source: UniProtKB
Response to dexamethasone Source: Ensembl
Response to drug Source: Ensembl
Response to fatty acid Source: UniProtKB
Response to starvation Source: UniProtKB
Response to water-immersion restraint stress Source: Ensembl
Tumor necrosis factor-mediated signaling pathway Source: UniProtKB
Cellular Location
Cytosol; Nucleus; Mitochondrion matrix; Mitochondrion outer membrane. Retention in the cytoplasm contributes to its inactivation (PubMed:10102273, PubMed:15084260, PubMed:16751106). Translocates to the nucleus upon oxidative stress and in the absence of survival factors (PubMed:10102273, PubMed:16751106). Translocates from the cytosol to the nucleus following dephosphorylation in response to autophagy-inducing stimuli (By similarity). Translocates in a AMPK-dependent manner into the mitochondrion in response to metabolic stress (PubMed:23283301, PubMed:29445193). Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (By similarity).
Involvement in disease
A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1.
PTM
In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-253 by AKT1/PKB (PubMed:10102273). This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm (PubMed:10102273). Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis (PubMed:10102273). Although AKT1/PKB doesn't appear to phosphorylate Ser-315 directly, it may activate other kinases that trigger phosphorylation at this residue (PubMed:10102273, PubMed:11154281). Phosphorylated by STK4/MST1 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation (PubMed:16751106). Phosphorylated by PIM1 (PubMed:18593906). Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization (PubMed:17711846). In response to metabolic stress, phosphorylated by AMPK on Ser-30 which mediates FOXO3 mitochondrial translocation (PubMed:29445193). Phosphorylation by MAPKAPK5 promotes nuclear localization and DNA-binding, leading to induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). Phosphorylated by CHUK/IKKA and IKBKB/IKKB (PubMed:15084260). TNF-induced inactivation of FOXO3 requires its phosphorylation at Ser-644 by IKBKB/IKKB which promotes FOXO3 retention in the cytoplasm, polyubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:15084260). May be dephosphorylated by calcineurin A on Ser-299 which abolishes FOXO3 transcriptional activity (By similarity). In cancer cells, ERK mediated-phosphorylation of Ser-12 is required for mitochondrial translocation of FOXO3 in response to metabolic stress or chemotherapeutic agents (PubMed:29445193). Phosphorylation at Ser-253 promotes its degradation by the proteasome (PubMed:30513302). Dephosphorylation at Ser-253 by protein phosphatase 2A (PPP2CA) promotes its stabilization; interaction with PPP2CA is enhanced by AMBRA1 (PubMed:30513302).
Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation (PubMed:21841822). Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress (By similarity). Deacetylated by SIRT3 (PubMed:23283301). Deacetylation by SIRT3 stimulates FOXO3-mediated mtDNA transcriptional activity in response to metabolic stress (PubMed:23283301).
Heavily methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-271. Methylation doesn't affect subcellular location.
Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation.
The N-terminus is cleaved following import into the mitochondrion.

Anti-Phospho-FOXO3 (Ser253) antibodies

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Target: Phospho-FOXO3 (Ser253)
Host: Rabbit
Antibody Isotype: IgG
Specificity: Human, Mouse, Rat, Monkey
Clone: D18H8
Application*: WB
For Research Use Only. Not For Clinical Use.
(P): Predicted
* Abbreviations
IFImmunofluorescence
IHImmunohistochemistry
IPImmunoprecipitation
WBWestern Blot
EELISA
MMicroarray
CIChromatin Immunoprecipitation
FFlow Cytometry
FNFunction Assay
IDImmunodiffusion
RRadioimmunoassay
TCTissue Culture
GSGel Supershift
NNeutralization
BBlocking
AActivation
IInhibition
DDepletion
ESELISpot
DBDot Blot
MCMass Cytometry/CyTOF
CTCytotoxicity
SStimulation
AGAgonist
APApoptosis
IMImmunomicroscopy
BABioassay
CSCostimulation
EMElectron Microscopy
IEImmunoelectrophoresis
PAPeptide Array
ICImmunocytochemistry
PEPeptide ELISA
MDMeDIP
SHIn situ hybridization
IAEnzyme Immunoassay
SEsandwich ELISA
PLProximity Ligation Assay
ECELISA(Cap)
EDELISA(Det)
BIBioimaging
IOImmunoassay
LFLateral Flow Immunoassay
LALuminex Assay
CImmunohistochemistry-Frozen Sections
PImmunohistologyp-Paraffin Sections
ISIntracellular Staining for Flow Cytometry
MSElectrophoretic Mobility Shift Assay
RIRNA Binding Protein Immunoprecipitation (RIP)
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