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). Homodimer (PubMed:18034774, PubMed:23055524). Homotetramer (PubMed:23055524). Binds RAB5A/Rab5 through an N-terminal domain. This interaction is essential for its recruitment to endosomal membranes as well as its role in cell proliferation (PubMed:15016378). Binds subunits of the NuRD/MeCP1 complex (PubMed:15016378). Interacts with FSHR; interaction is independent of follicle stimulating hormone stimulation (PubMed:17030088). Interacts with APPL1; the interaction is decreased by adiponectin in a time-dependent manner (PubMed:17030088, PubMed:18034774). Forms a complex comprising APPL1, RUVBL2, CTNNB1, HDAC1 and HDAC2; interaction reduces interaction between CTNNB1, HDAC1, HDAC2 and RUVBL2 leading to the decrease of deacetylase activity of this complex; affects the recruitment of repressive complexes to the Wnt target genes (PubMed:19433865). Interacts (via BAR domain) with TBC1D1; interaction is dependent of TBC1D1 phosphorylation at 'Ser-235'; interaction diminishes the phosphorylation of TBC1D1 at 'Thr-596', resulting in inhibition of SLC2A4 translocation and glucose uptake (PubMed:24879834). Interacts with ANXA2; targets APPL2 to endosomes and acting in parallel to RAB5A (PubMed:21645192). Interacts with RAB31 (in GTP-bound form); interaction contributes to or enhances recruitment of APPL2 to the phagosomes; interaction enhances Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages (PubMed:23055524). Interacts with PIK3R1; forms a complex with PIK3R1 and APPL1 (By similarity). Interacts (via BAR domain) with ADIPOR1; hinders the accessibility of APPL1 to ADIPOR1; negatively regulates adiponectin signaling; ADIPOQ dissociates this interaction and facilitates the recruitment of APPL1 to ADIPOR1 (By similarity). Interacts (via BAR domain) with ADIPOR2; ADIPOQ dissociates this interaction (By similarity). 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). High levels in brain, heart, kidney and skeletal muscle. The BAR domain is necessary and sufficient for mediating homotypic and heterotypic interactions; associates with cytoplasmic membrane structures; mediates interaction with TBC1D1 and ADIPOR1 (PubMed:18034774) (By similarity). The PH and PID domains mediate phosphoinositide binding (PubMed:18034774). The PID domain mediates phosphatidylserine binding and allows localization to cytosolic membrane structures and nucleus (PubMed:18034774). The PH domain allows localization to the plasma membrane, cytosolic vesicles and distinct nuclear and perinuclear structures and is sufficient for RUVBL2 interaction (PubMed:18034774, PubMed:19433865). A chromosomal aberration involving APPL2/DIP13B is found in patients with chromosome 22q13.3 deletion syndrome. Translocation t(12;22)(q24.1;q13.3) with SHANK3/PSAP2.