UniProt functional annotation for P37231



	UniProt functional annotation for P37231

UniProt code: P37231.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity). {ECO:0000250|UniProtKB:P37238, ECO:0000269|PubMed:16150867, ECO:0000269|PubMed:20829347, ECO:0000269|PubMed:23525231, ECO:0000269|PubMed:9065481}.

Function: (Microbial infection) Upon treatment with M.tuberculosis or its lipoprotein LpqH, phosphorylation of MAPK p38 and IL-6 production are modulated, probably via this protein. {ECO:0000269|PubMed:25504154}.

Activity regulation: PDPK1 activates its transcriptional activity independently of its kinase activity. {ECO:0000269|PubMed:16150867}.

Subunit: Interacts with FOXO1 (acetylated form) (By similarity). Heterodimer with other nuclear receptors, such as RXRA. The heterodimer with the retinoic acid receptor RXRA is called adipocyte-specific transcription factor ARF6. Interacts with NCOA6 coactivator, leading to a strong increase in transcription of target genes. Interacts with coactivator PPARBP, leading to a mild increase in transcription of target genes. Interacts with NOCA7 in a ligand-inducible manner. Interacts with NCOA1 and NCOA2 LXXLL motifs. Interacts with ASXL1, ASXL2, DNTTIP2, FAM120B, MAP2K1/MEK1, NR0B2, PDPK1, PRDM16, PRMT2 and TGFB1I1. Interacts (when activated by agonist) with PPP5C. Interacts with HELZ2 and THRAP3; the interaction stimulates the transcriptional activity of PPARG. Interacts with PER2, the interaction is ligand dependent and blocks PPARG recruitment to target promoters. Interacts with NOCT. Interacts with ACTN4. Interacts (when in the liganded conformation) with GPS2 (By similarity). Interacts with CRY1 and CRY2 in a ligand-dependent manner (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). {ECO:0000250|UniProtKB:P37238, ECO:0000269|PubMed:10681503, ECO:0000269|PubMed:11587644, ECO:0000269|PubMed:11971969, ECO:0000269|PubMed:12039952, ECO:0000269|PubMed:12672231, ECO:0000269|PubMed:15047147, ECO:0000269|PubMed:15056000, ECO:0000269|PubMed:15258145, ECO:0000269|PubMed:15687259, ECO:0000269|PubMed:15974597, ECO:0000269|PubMed:15976031, ECO:0000269|PubMed:16150867, ECO:0000269|PubMed:16239304, ECO:0000269|PubMed:16451087, ECO:0000269|PubMed:16640330, ECO:0000269|PubMed:16919947, ECO:0000269|PubMed:17101779, ECO:0000269|PubMed:20078863, ECO:0000269|PubMed:21047783, ECO:0000269|PubMed:22351778, ECO:0000269|PubMed:23525231, ECO:0000269|PubMed:9744270}.

Subcellular location: Nucleus. Cytoplasm. Note=Redistributed from the nucleus to the cytosol through a MAP2K1/MEK1-dependent manner. NOCT enhances its nuclear translocation.

Tissue specificity: Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary. {ECO:0000269|PubMed:9065481}.

Induction: (Microbial infection) Expression increases when incubated with M.tuberculosis or its lipoprotein LpqH; induction is TLR2- dependent (at protein level). {ECO:0000269|PubMed:25504154}.

Domain: The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. {ECO:0000305|PubMed:30468856}.

Ptm: O-GlcNAcylation at Thr-84 reduces transcriptional activity in adipocytes. {ECO:0000250|UniProtKB:P37238}.

Ptm: Phosphorylated in basal conditions and dephosphorylated when treated with the ligand. May be dephosphorylated by PPP5C. The phosphorylated form may be inactive and dephosphorylation at Ser-112 induces adipogenic activity (By similarity). {ECO:0000250}.

Polymorphism: Genetic variations in PPARG define the body mass index quantitative trait locus 1 (BMIQ1) [MIM:606641]. The body max index (BMI) reflects the amount of fat, lean mass, and body build. {ECO:0000269|PubMed:10523018, ECO:0000269|PubMed:14569127}.

Polymorphism: Genetic variations in PPARG influence the carotid intimal medial thickness (CIMT) [MIM:609338]. CIMT is a measure of atherosclerosis that is independently associated with traditional atherosclerotic cardiovascular disease risk factors and coronary atherosclerotic burden. 35 to 45% of the variability in multivariable- adjusted CIMT is explained by genetic factors. {ECO:0000269|PubMed:15356014}.

Disease: Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. {ECO:0000269|PubMed:10394368}.

Disease: Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:9753710}. Note=Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Disease: Lipodystrophy, familial partial, 3 (FPLD3) [MIM:604367]: A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. {ECO:0000269|PubMed:11788685, ECO:0000269|PubMed:12453919}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Glioma 1 (GLM1) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:10851250}. Note=Disease susceptibility may be associated with variants affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.

Miscellaneous: [Isoform 3]: Exhibits dominant negative activity over isoform 1. {ECO:0000305}.

Similarity: Belongs to the nuclear hormone receptor family. NR1 subfamily. {ECO:0000305}.

Sequence caution: Sequence=AAN38992.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=BAA23354.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; Sequence=BAF83270.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=CAA62153.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity). {ECO:0000250\|UniProtKB:P37238, ECO:0000269\|PubMed:16150867, ECO:0000269\|PubMed:20829347, ECO:0000269\|PubMed:23525231, ECO:0000269\|PubMed:9065481}.



Function:		(Microbial infection) Upon treatment with M.tuberculosis or its lipoprotein LpqH, phosphorylation of MAPK p38 and IL-6 production are modulated, probably via this protein. {ECO:0000269\|PubMed:25504154}.


Activity regulation:		PDPK1 activates its transcriptional activity independently of its kinase activity. {ECO:0000269\|PubMed:16150867}.
Subunit:		Interacts with FOXO1 (acetylated form) (By similarity). Heterodimer with other nuclear receptors, such as RXRA. The heterodimer with the retinoic acid receptor RXRA is called adipocyte-specific transcription factor ARF6. Interacts with NCOA6 coactivator, leading to a strong increase in transcription of target genes. Interacts with coactivator PPARBP, leading to a mild increase in transcription of target genes. Interacts with NOCA7 in a ligand-inducible manner. Interacts with NCOA1 and NCOA2 LXXLL motifs. Interacts with ASXL1, ASXL2, DNTTIP2, FAM120B, MAP2K1/MEK1, NR0B2, PDPK1, PRDM16, PRMT2 and TGFB1I1. Interacts (when activated by agonist) with PPP5C. Interacts with HELZ2 and THRAP3; the interaction stimulates the transcriptional activity of PPARG. Interacts with PER2, the interaction is ligand dependent and blocks PPARG recruitment to target promoters. Interacts with NOCT. Interacts with ACTN4. Interacts (when in the liganded conformation) with GPS2 (By similarity). Interacts with CRY1 and CRY2 in a ligand-dependent manner (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). {ECO:0000250\|UniProtKB:P37238, ECO:0000269\|PubMed:10681503, ECO:0000269\|PubMed:11587644, ECO:0000269\|PubMed:11971969, ECO:0000269\|PubMed:12039952, ECO:0000269\|PubMed:12672231, ECO:0000269\|PubMed:15047147, ECO:0000269\|PubMed:15056000, ECO:0000269\|PubMed:15258145, ECO:0000269\|PubMed:15687259, ECO:0000269\|PubMed:15974597, ECO:0000269\|PubMed:15976031, ECO:0000269\|PubMed:16150867, ECO:0000269\|PubMed:16239304, ECO:0000269\|PubMed:16451087, ECO:0000269\|PubMed:16640330, ECO:0000269\|PubMed:16919947, ECO:0000269\|PubMed:17101779, ECO:0000269\|PubMed:20078863, ECO:0000269\|PubMed:21047783, ECO:0000269\|PubMed:22351778, ECO:0000269\|PubMed:23525231, ECO:0000269\|PubMed:9744270}.
Subcellular location:		Nucleus. Cytoplasm. Note=Redistributed from the nucleus to the cytosol through a MAP2K1/MEK1-dependent manner. NOCT enhances its nuclear translocation.
Tissue specificity:		Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary. {ECO:0000269\|PubMed:9065481}.
Induction:		(Microbial infection) Expression increases when incubated with M.tuberculosis or its lipoprotein LpqH; induction is TLR2- dependent (at protein level). {ECO:0000269\|PubMed:25504154}.
Domain:		The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. {ECO:0000305\|PubMed:30468856}.
Ptm:		O-GlcNAcylation at Thr-84 reduces transcriptional activity in adipocytes. {ECO:0000250\|UniProtKB:P37238}.
Ptm:		Phosphorylated in basal conditions and dephosphorylated when treated with the ligand. May be dephosphorylated by PPP5C. The phosphorylated form may be inactive and dephosphorylation at Ser-112 induces adipogenic activity (By similarity). {ECO:0000250}.
Polymorphism:		Genetic variations in PPARG define the body mass index quantitative trait locus 1 (BMIQ1) [MIM:606641]. The body max index (BMI) reflects the amount of fat, lean mass, and body build. {ECO:0000269\|PubMed:10523018, ECO:0000269\|PubMed:14569127}.
Polymorphism:		Genetic variations in PPARG influence the carotid intimal medial thickness (CIMT) [MIM:609338]. CIMT is a measure of atherosclerosis that is independently associated with traditional atherosclerotic cardiovascular disease risk factors and coronary atherosclerotic burden. 35 to 45% of the variability in multivariable- adjusted CIMT is explained by genetic factors. {ECO:0000269\|PubMed:15356014}.
Disease:		Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. {ECO:0000269\|PubMed:10394368}.
Disease:		Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269\|PubMed:9753710}. Note=Disease susceptibility may be associated with variants affecting the gene represented in this entry.
Disease:		Lipodystrophy, familial partial, 3 (FPLD3) [MIM:604367]: A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. {ECO:0000269\|PubMed:11788685, ECO:0000269\|PubMed:12453919}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Glioma 1 (GLM1) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269\|PubMed:10851250}. Note=Disease susceptibility may be associated with variants affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
Miscellaneous:		[Isoform 3]: Exhibits dominant negative activity over isoform 1. {ECO:0000305}.
Similarity:		Belongs to the nuclear hormone receptor family. NR1 subfamily. {ECO:0000305}.
Sequence caution:		Sequence=AAN38992.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=BAA23354.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; Sequence=BAF83270.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=CAA62153.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};