APPL2
Description
The APPL2 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2) is a protein-coding gene located on chromosome 12.
DCC-interacting protein 13-beta is a protein that in humans is encoded by the APPL2 gene.
APPL2 is a multifunctional adapter protein that interacts with various membrane receptors, nuclear factors, and signaling proteins to regulate numerous cellular processes, including cell proliferation, immune response, endosomal trafficking, and cell metabolism. It plays a role in cell proliferation by interacting with RAB5A and components of the NuRD/MeCP1 complex. In immune responses, APPL2 modulates phagocytosis, inflammatory responses, and innate immunity. For instance, in macrophages, it enhances Fc-gamma receptor-mediated phagocytosis through interaction with RAB31, leading to activation of PI3K/Akt signaling. APPL2 also modulates inflammatory responses by regulating TLR4 signaling and the nuclear translocation of RELA/NF-kappa-B p65, influencing the secretion of pro- and anti-inflammatory cytokines. It can act as a negative regulator of innate immune responses by inhibiting AKT1 signaling through a complex with APPL1 and PIK3R1. APPL2 participates in endosomal trafficking, specifically by transporting TGFBR1 from endosomes to the nucleus. In cell metabolism, it regulates adiponectin and insulin signaling pathways and plays a role in adaptive thermogenesis. In muscle, APPL2 negatively regulates adiponectin-simulated glucose uptake and fatty acid oxidation by inhibiting adiponectin signaling through APPL1 sequestration, antagonizing APPL1's action. It also negatively regulates insulin-induced plasma membrane recruitment of GLUT4 and glucose uptake by interacting with TBC1D1. APPL2 contributes to cold and diet-induced adaptive thermogenesis by activating ventromedial hypothalamus (VMH) neurons through AMPK inhibition, which enhances sympathetic outflow to subcutaneous white adipose tissue (sWAT), promoting sWAT beiging and cold tolerance. Additionally, APPL2 participates in other signaling pathways, such as Wnt/beta-catenin, HGF, and glucocorticoid receptor signaling. It acts as a positive regulator of beta-catenin/TCF-dependent transcription through direct interaction with RUVBL2/reptin, relieving RUVBL2-mediated repression of beta-catenin/TCF target genes by modulating interactions within the beta-catenin-reptin-HDAC complex. APPL2 may affect adult neurogenesis in the hippocampus and olfactory system by regulating the sensitivity of the glucocorticoid receptor. It is required for fibroblast migration through HGF cell signaling.
APPL2 is also known as DIP13B.
Associated Diseases
- hypertriglyceridemia 2
- hemoglobin D disease
- cholesterol-ester transfer protein deficiency
- hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
- primary familial polycythemia due to EPO receptor mutation
- hemoglobin E disease
- dominant beta-thalassemia
- hemoglobin E-beta-thalassemia syndrome
- delta-beta-thalassemia
- hemolytic anemia due to diphosphoglycerate mutase deficiency
