Disease relevance of APPL1

• Brain injury induces APPL upregulation in Drosophila neurons, correlating with increased post-traumatic mortality in appl(d) mutant flies [1].

High impact information on APPL1

• APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment [2].
• Both APPL1 and APPL2 are essential for cell proliferation and their function requires Rab5 binding [2].
• In response to extracellular stimuli such as EGF and oxidative stress, APPL1 translocates from the membranes to the nucleus where it interacts with the nucleosome remodeling and histone deacetylase multiprotein complex NuRD/MeCP1, an established regulator of chromatin structure and gene expression [2].
• These results demonstrate a key function for APPL1 in adiponectin signalling and provide a molecular mechanism for the insulin sensitizing function of adiponectin [3].
• GIPC, but not APPL, dissociates from these peripheral endosomes prior to or during their trafficking from the cell periphery to the juxtanuclear region, where they acquire EEA1 [4].

Biological context of APPL1

• Furthermore, the APPL gene was mapped to human chromosome 3p14.3-p21.1, where deletions and other rearrangements have often been reported in a variety of tumor types [5].
• Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2 [5].
• APPL suppresses androgen receptor transactivation via potentiating Akt activity [6].
• We also observed that APPL could further enhance the Akt-mediated suppression of AR transactivation and AR target gene using the reporter gene and Northern blot assay [6].
• The phosphorylation status of members of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway was also examined because of the proposed role of APPL1 in the antiapoptotic PI3K/Akt pathway [7].

Anatomical context of APPL1

• Our findings identify an endosomal compartment bearing Rab5 and APPL proteins as an intermediate in signaling between the plasma membrane and the nucleus [2].
• APPL is highly expressed in skeletal muscle, heart, ovary and pancreas, tissues in which AKT2 mRNA is abundant [5].

Associations of APPL1 with chemical compounds

• The DIP13 alpha protein has a pleckstrin homology domain and a phosphotyrosine binding domain [8].
• Expression of full-length APPL1 and its N terminus suppressed insulin-stimulated 2-deoxyglucose uptake and Glut4 translocation to roughly the same extent (40-60%) [9].

Physical interactions of APPL1

• Removal of the DCC-interacting domain on DIP13 alpha abolishes its ability to enhance DCC-induced apoptosis [8].
• APPL1 was isolated as a binding partner for the TrkA-interacting protein GIPC1 from rat brain lysate by mass spectrometry [10].

Regulatory relationships of APPL1

• Inhibition of endogenous DIP13 alpha expression by small interfering RNA blocks DCC-induced apoptosis [8].

Other interactions of APPL1

• The identification of APPL may facilitate further analysis of the physiological and oncogenic activities of AKT2 [5].
• Using this technique, we identified a novel interactor, designated APPL, which contains a pleckstrin homology (PH) domain, a phosphotyrosine binding (PTB) domain and a leucine zipper, classes of motifs defined in signaling molecules as functional interaction domains with specific targets [5].
• The identification of APPL1 as a potential interactor with FSHR and the finding that FOXO1a is phosphorylated in response to FSH provide a possible link between FSH and PI3K/Akt signaling, which may help to delineate a survival mechanism whereby FSH selects the dominant follicle to survive [7].
• Mediation of the DCC apoptotic signal by DIP13 alpha [8].
• Moreover, APPL1 and APPL2 associate with one another via the N-terminus of APPL1, presumably via the Bin-Amphiphysin-Rvs (BAR) domain [11].

Analytical, diagnostic and therapeutic context of APPL1

• Isolation of endosomal fractions by high-resolution centrifugation determined that APPL1, GIPC1, and phosphorylated TrkA are enriched in the same fractions [10].

References