UniProt functional annotation for O00213



	UniProt functional annotation for O00213

UniProt code: O00213.

Organism: Homo sapiens (Human).

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

Function: Transcription coregulator that can have both coactivator and corepressor functions. Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain. Plays a central role in the response to DNA damage by translocating to the nucleus and inducing apoptosis. May act by specifically recognizing and binding histone H2AX phosphorylated on 'Tyr-142' (H2AXY142ph) at double-strand breaks (DSBs), recruiting other pro-apoptosis factors such as MAPK8/JNK1. Required for histone H4 acetylation at double-strand breaks (DSBs). Its ability to specifically bind modified histones and chromatin modifying enzymes such as KAT5/TIP60, probably explains its transcription activation activity. Functions in association with TSHZ3, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4. Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s). {ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:18468999, ECO:0000269|PubMed:18922798, ECO:0000269|PubMed:19234442, ECO:0000269|PubMed:19343227, ECO:0000269|PubMed:25342469}.

Subunit: Component of a complex, at least composed of APBB1, RASD1/DEXRAS1 and APP. Interacts (via PID domain 2) with APP (with the intracellular domain of the amyloid-beta precursor protein). Interacts (via PID domain 2) with RASD1/DEXRAS1; impairs the transcription activation activity. Interacts (via PID domain 1) with KAT5/TIP60. Interacts (via the WW domain) with the proline-rich region of APBB1IP. Interacts with TSHZ1 and TSHZ2 (By similarity). Interacts (via the WW domain) with histone H2AX (when phosphorylated on 'Tyr-142') and the proline-rich region of ENAH. Interacts with MAPK8. Interacts (via PID domain 1) with TSHZ3 (via homeobox domain). Interacts with SET. Found in a trimeric complex with HDAC1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3. Interacts (via WWW domain) with NEK6. Interacts (via WWW domain) with ABL1. Interacts with RNF157 (PubMed:25342469). {ECO:0000250, ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:17512906, ECO:0000269|PubMed:17686488, ECO:0000269|PubMed:18468999, ECO:0000269|PubMed:18833287, ECO:0000269|PubMed:18922798, ECO:0000269|PubMed:19234442, ECO:0000269|PubMed:19343227, ECO:0000269|PubMed:25342469}.

Subcellular location: Cell membrane. Cytoplasm. Nucleus. Cell projection, growth cone {ECO:0000250}. Nucleus speckle. Note=Colocalizes with TSHZ3 in axonal growth cone (By similarity). In normal conditions, it mainly localizes to the cytoplasm, while a small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP. Colocalizes with TSHZ3 in the nucleus. Colocalizes with NEK6 at the nuclear speckles. Phosphorylation at Ser- 610 by SGK1 promotes its localization to the nucleus (By similarity). {ECO:0000250}.

Tissue specificity: Highly expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease. {ECO:0000269|PubMed:19343227}.

Ptm: Polyubiquitination by RNF157 leads to degradation by the proteasome (PubMed:25342469). {ECO:0000269|PubMed:25342469}.

Ptm: Phosphorylation at Ser-610 by SGK1 promotes its localization to the nucleus (By similarity). Phosphorylated following nuclear translocation. Phosphorylation at Tyr-547 by ABL1 enhances transcriptional activation activity and reduces the affinity for RASD1/DEXRAS1. {ECO:0000250, ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:18922798}.

Miscellaneous: [Isoform 4]: Expressed preferentially in the brain. {ECO:0000305}.

Sequence caution: Sequence=CAD98057.1; Type=Erroneous initiation; Note=Extended 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:		Transcription coregulator that can have both coactivator and corepressor functions. Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain. Plays a central role in the response to DNA damage by translocating to the nucleus and inducing apoptosis. May act by specifically recognizing and binding histone H2AX phosphorylated on 'Tyr-142' (H2AXY142ph) at double-strand breaks (DSBs), recruiting other pro-apoptosis factors such as MAPK8/JNK1. Required for histone H4 acetylation at double-strand breaks (DSBs). Its ability to specifically bind modified histones and chromatin modifying enzymes such as KAT5/TIP60, probably explains its transcription activation activity. Functions in association with TSHZ3, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4. Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s). {ECO:0000269\|PubMed:15031292, ECO:0000269\|PubMed:18468999, ECO:0000269\|PubMed:18922798, ECO:0000269\|PubMed:19234442, ECO:0000269\|PubMed:19343227, ECO:0000269\|PubMed:25342469}.


Subunit:		Component of a complex, at least composed of APBB1, RASD1/DEXRAS1 and APP. Interacts (via PID domain 2) with APP (with the intracellular domain of the amyloid-beta precursor protein). Interacts (via PID domain 2) with RASD1/DEXRAS1; impairs the transcription activation activity. Interacts (via PID domain 1) with KAT5/TIP60. Interacts (via the WW domain) with the proline-rich region of APBB1IP. Interacts with TSHZ1 and TSHZ2 (By similarity). Interacts (via the WW domain) with histone H2AX (when phosphorylated on 'Tyr-142') and the proline-rich region of ENAH. Interacts with MAPK8. Interacts (via PID domain 1) with TSHZ3 (via homeobox domain). Interacts with SET. Found in a trimeric complex with HDAC1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3. Interacts (via WWW domain) with NEK6. Interacts (via WWW domain) with ABL1. Interacts with RNF157 (PubMed:25342469). {ECO:0000250, ECO:0000269\|PubMed:15031292, ECO:0000269\|PubMed:17512906, ECO:0000269\|PubMed:17686488, ECO:0000269\|PubMed:18468999, ECO:0000269\|PubMed:18833287, ECO:0000269\|PubMed:18922798, ECO:0000269\|PubMed:19234442, ECO:0000269\|PubMed:19343227, ECO:0000269\|PubMed:25342469}.
Subcellular location:		Cell membrane. Cytoplasm. Nucleus. Cell projection, growth cone {ECO:0000250}. Nucleus speckle. Note=Colocalizes with TSHZ3 in axonal growth cone (By similarity). In normal conditions, it mainly localizes to the cytoplasm, while a small fraction is tethered to the cell membrane via its interaction with APP. Following exposure to DNA damaging agents, it is released from cell membrane and translocates to the nucleus. Nuclear translocation is under the regulation of APP. Colocalizes with TSHZ3 in the nucleus. Colocalizes with NEK6 at the nuclear speckles. Phosphorylation at Ser- 610 by SGK1 promotes its localization to the nucleus (By similarity). {ECO:0000250}.
Tissue specificity:		Highly expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease. {ECO:0000269\|PubMed:19343227}.
Ptm:		Polyubiquitination by RNF157 leads to degradation by the proteasome (PubMed:25342469). {ECO:0000269\|PubMed:25342469}.
Ptm:		Phosphorylation at Ser-610 by SGK1 promotes its localization to the nucleus (By similarity). Phosphorylated following nuclear translocation. Phosphorylation at Tyr-547 by ABL1 enhances transcriptional activation activity and reduces the affinity for RASD1/DEXRAS1. {ECO:0000250, ECO:0000269\|PubMed:15031292, ECO:0000269\|PubMed:18922798}.
Miscellaneous:		[Isoform 4]: Expressed preferentially in the brain. {ECO:0000305}.
Sequence caution:		Sequence=CAD98057.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};