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) . Involved in hippocampal neurite branching and neuromuscular junction formation, as a result plays a role in spatial memory functioning (By similarity). Plays a role in the maintenance of lens transparency (By similarity). May play a role in muscle cell strength (By similarity). Acts as a molecular adapter that functions in neurite outgrowth by activating the RAC1-ARF6 axis upon insulin treatment .
Subcellular locations: Cell membrane, Cytoplasm, Nucleus, Cell projection, Growth cone, Nucleus speckle
Colocalizes with TSHZ3 in axonal growth cone (By similarity). Colocalizes with TSHZ3 in the nucleus . 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 NEK6 at the nuclear speckles . Phosphorylation at Ser-610 by SGK1 promotes its localization to the nucleus (By similarity).
Highly expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease.
Expressed preferentially in the brain.