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 (By similarity) (PubMed:25328665, PubMed:25568335, PubMed:27219021). Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex (By similarity). Functions as a positive regulator of innate immune response via activation of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1 (PubMed:25328665). Inhibits Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages (PubMed:25568335). Regulates TLR4 signaling in activated macrophages (PubMed:27219021). Involved in trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner. Plays a role in cell metabolism by regulating adiponecting and insulin signaling pathways (By similarity). Required for fibroblast migration through HGF cell signaling (PubMed:26445298). 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 (By similarity). Homodimer. 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. Binds DCC and the catalytic domain of the inactive form of AKT2 through its PID domain. Binds PIK3CA and subunits of the NuRD/MeCP1 complex (By similarity). Interacts with OCRL and INPP5B (PubMed:20133602) (By similarity). Interacts with NTRK2 (PubMed:21849472). Interacts with APPL2; interaction is independent of follicle stimulating hormone stimulation; interaction is decreased by adiponectin in a time-dependent manner (PubMed:25328665). Forms a complex with APPL2 and RUVBL2. Forms a complex comprising APPL2, 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. Interacts with ANXA2. Interacts with TGFBR1; interaction is TGF beta dependent; mediates trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner. Interacts with PRKCZ (By similarity). Interacts with PIK3R1 and APPL2 (PubMed:25328665). Interacts with ADIPOR1; ADIPOQ enhances this interaction; inhibites adiponectin-stimulated binding of APPL2 to ADIPOR1 (PubMed:19661063). Early endosomal membrane-bound and nuclear. Translocated into the nucleus upon release from endosomal membranes following internalization of EGF. Expressed in insulin-target tissues including skeletal muscle, liver, fat, and brain. Overexpression of an N-terminal domain (residues 1-319) or a C-terminal region (residues 273-707) has a proapoptotic effect. The F&H motif, an approximately 12-13 amino-acid sequence centered around Phe and His residues, is essential for binding to OCRL and INPP5B. Phosphorylation at Ser-410 by PKA severely impairs binding to OCRL. Reduced survival rate after injection of LPS (PubMed:25328665). Appl1 and Appl2 double knockout mice are viable and grossly normal with regard to reproductive potential and postnatal growth (PubMed:26445298). Extended N-terminus.