APPL1

The protein encoded by this gene has been shown to be involved in the regulation of cell proliferation, and in the crosstalk between the adiponectin signalling and insulin signalling pathways. The encoded protein binds many other proteins, including RAB5A, DCC, AKT2, PIK3CA, adiponectin receptors, and proteins of the NuRD/MeCP1 complex. This protein is found associated with endosomal membranes, but can be released by EGF and translocated to the nucleus. [provided by RefSeq, Jul 2008]

Full Name

Adaptor Protein, Phosphotyrosine Interacting With PH Domain And Leucine Zipper 1

Function

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:26073777, PubMed:19661063, PubMed:10490823). Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex (PubMed:15016378). Functions as a positive regulator of innate immune response via activation of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1 (By similarity). Inhibits Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages (By similarity). Regulates TLR4 signaling in activated macrophages (By similarity). Involved in trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner (PubMed:26583432). Plays a role in cell metabolism by regulating adiponecting and insulin signaling pathways (PubMed:26073777, PubMed:19661063, PubMed:24879834). Required for fibroblast migration through HGF cell signaling (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).

Biological Process

Adiponectin-activated signaling pathway Source: UniProtKB
Cell cycle Source: UniProtKB-KW
Cellular response to hepatocyte growth factor stimulus Source: UniProtKB
Extrinsic apoptotic signaling pathway in absence of ligand Source: Reactome
Insulin receptor signaling pathway Source: UniProtKB
Negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis Source: UniProtKB
Positive regulation of cytokine production involved in inflammatory response Source: UniProtKB
Positive regulation of glucose import Source: UniProtKB
Positive regulation of macropinocytosis Source: UniProtKB
Positive regulation of melanin biosynthetic process 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 glucose import Source: BHF-UCL
Regulation of innate immune response Source: UniProtKB
Regulation of protein localization to plasma membrane Source: BHF-UCL
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

Cellular Location

Cytoplasm; Early endosome membrane; Endosome; Nucleus; Ruffle; Phagosome. Early endosomal membrane-bound and nuclear. Translocated into the nucleus upon release from endosomal membranes following internalization of EGF.

Involvement in disease

Maturity-onset diabetes of the young 14 (MODY14): A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.

PTM

Phosphorylation at Ser-410 by PKA severely impairs binding to OCRL.