APPL2

APPL2 is one of two effectors of the small GTPase RAB5A/Rab5, which are involved in a signal transduction pathway. Both effectors contain an N-terminal Bin/Amphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain, and a C-terminal phosphoty

adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2

Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism (PubMed:26583432, PubMed:15016378, PubMed:24879834). Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex (PubMed:15016378). Plays a role in immune response by modulating phagocytosis, inflammatory and innate immune responses. In macrophages, enhances Fc-gamma receptor-mediated phagocytosis through interaction with RAB31 leading to activation of PI3K/Akt signaling. In response to LPS, modulates inflammatory responses by playing a key role on the regulation of TLR4 signaling and in the nuclear translocation of RELA/NF-kappa-B p65 and the secretion of pro- and anti-inflammatory cytokines. Also functions as a negative regulator of innate immune response via inhibition of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1 (By similarity). Plays a role in endosomal trafficking of TGFBR1 from the endosomes to the nucleus (PubMed:26583432). Plays a role in cell metabolism by regulating adiponecting ans insulin signaling pathways and adaptative thermogenesis (PubMed:24879834) (By similarity). In muscle, negatively regulates adiponectin-simulated glucose uptake and fatty acid oxidation by inhibiting adiponectin signaling pathway through APPL1 sequestration thereby antagonizing APPL1 action (By similarity). In muscles, negativeliy regulates insulin-induced plasma membrane recruitment of GLUT4 and glucose uptake through interaction with TBC1D1 (PubMed:24879834). Plays a role in cold and diet-induced adaptive thermogenesis by activating ventromedial hypothalamus (VMH) neurons throught AMPK inhibition which enhances sympathetic outflow to subcutaneous white adipose tissue (sWAT), sWAT beiging and cold tolerance (By similarity). Also plays a role in other signaling pathways namely Wnt/beta-catenin, HGF and glucocorticoid receptor signaling (PubMed:19433865) (By similarity). Positive regulator of beta-catenin/TCF-dependent transcription through direct interaction with RUVBL2/reptin resulting in the relief of RUVBL2-mediated repression of beta-catenin/TCF target genes by modulating the interactions within the beta-catenin-reptin-HDAC complex (PubMed:19433865). May affect adult neurogenesis in hippocampus and olfactory system via regulating the sensitivity of glucocorticoid receptor. Required for fibroblast migration through HGF cell signaling (By similarity).

Adiponectin-activated signaling pathway Source: UniProtKB
Cell cycle Source: UniProtKB-KW
Cellular response to hepatocyte growth factor stimulus Source: UniProtKB
Cold acclimation Source: UniProtKB
Diet induced thermogenesis Source: UniProtKB
Glucose homeostasis Source: UniProtKB
Negative regulation of cellular response to insulin stimulus Source: UniProtKB
Negative regulation of cytokine production involved in inflammatory response Source: UniProtKB
Negative regulation of fatty acid oxidation Source: UniProtKB
Negative regulation of glucose import Source: UniProtKB
Negative regulation of neural precursor cell proliferation Source: UniProtKB
Negative regulation of neurogenesis Source: UniProtKB
Positive regulation of cold-induced thermogenesis Source: UniProtKB
Positive regulation of Fc-gamma receptor signaling pathway involved in phagocytosis Source: UniProtKB
Positive regulation of macropinocytosis Source: UniProtKB
Positive regulation of phagocytosis, engulfment Source: UniProtKB
Protein homotetramerization Source: UniProtKB
Protein import into nucleus Source: UniProtKB
Regulation of fibroblast migration Source: UniProtKB
Regulation of G1/S transition of mitotic cell cycle Source: UniProtKB
Regulation of innate immune response Source: UniProtKB
Regulation of toll-like receptor 4 signaling pathway Source: UniProtKB
Signaling Source: GO_Central
Signal transduction Source: UniProtKB
Transforming growth factor beta receptor signaling pathway Source: UniProtKB

Cytoplasm; Early endosome membrane; Endosome membrane; Cell membrane; Ruffle membrane; Cell membrane; Nucleus; Phagosome; Ruffle; phagosome membrane. Early endosomal membrane-bound and nuclear (PubMed:15016378). Translocated into the nucleus upon release from endosomal membranes following internalization of EGF (PubMed:15016378). Associates dynamically with cytoplasmic membrane structures that undergo changes in shape, movement, fusion and fission events (PubMed:18034774). PI(4,5)P2 levels are important for membrane association of APPL2 (PubMed:18034774). Absent of endosome in macrophage. Colocalized with RAB31 at early-stage phagosome (By similarity). Localized on macropinosomes in LPS-activated macrophages. Associated with membrane domains in contact with pathogens and pathogen-derived ligands like LPS. First recruited to the ruffles, and accumulates on macropinosomes (By similarity).