Role of APPL in endosomal signaling pathways Endosomes consi

Role of APPL in endosomal signaling pathways Endosomes consist of distinct membrane subdomains within individual organelles and assist in the translation of extracellular stimuli via cytoplasmic transduction cascades to the nucleus [3], [74]. Endosomal abnormalities are associated with the pathogenesis of neurological diseases such as Alzheimer's disease and Down Syndrome [75]. The small GTPase Rab 5 is a key factor of membrane transportation from the plasma membrane to the early endosomes, and thus it acts as an essential regulator of cell endolysis and endosomal trafficking [3]. APPL1 and APPL2 are both localized at the cytoplasmic and early endosomal membranes and have been identified to play critical roles in Rab 5-dependent nuclear signal transduction via the endosome [3]. In response to extracellular stimuli (e.g., EGF treatment), APPLs undergo redistribution cycles between endosomes and the nucleus. As a binding partner and prostaglandin receptor of Rab 5, APPL1 is released from the membranes by Rab 5-GTP activation and interacts with components of the nucleosome remodeling and histone deacetylase multiprotein complex NuRD-MeCP1, contributing to cell proliferation [3], [15]. Therefore, APPL1 functions as a hub linker from the endosome to the nucleus by mediating the Rab 5-trigged signaling pathway. Rab 5-APPL1 associated endosomal signaling is involved in several neuron-related disorders. Increased amyloid precursor protein (APP) and its cleaved product, β-cleaved carboxy-terminal fragment (βCTF), are associated with the pathogenesis of Alzheimer's disease and Down syndrome [7]. Endosomes are highly active APP processing sites correlated with up-regulation of Rab 5 [7]. By selectively binding to the PTB domain of APPL1 via its YENPTY domain, βCTF recruits APPL1 to Rab 5 endosomes, where APPL1 stabilizes active Rab 5-GTP leading to pathologically accelerated endocytosis, endosome swelling, and selectively impaired axonal transport of Rab 5 endosomes. Nevertheless, these effects could be reversed by knockdown of APPL1 [7]. Therefore, as an essential mediator of Rab 5 activation, APPL1 could be a potential therapeutic target for Alzheimer's disease and Down Syndrome. APPL associated endosomes also participate in growth factor receptor trafficking and signaling. In the Ras-induced macropinocytic pathway, APPL1 defines a compartment that immediately follows fission from the cell surface and subsequently becomes mature in canonical phosphatidylinositol 3-phosphate (PI3P) positive endosomes [76]. Most APPL endosomes are precursors of classical PI3P positive endosomes, which, in turn, cause APPLs to move back to endocytic vesicles and macropinosomes [76]. PI3P production on endosomes functions as a switch leading to the recruitment of PI3P and Rab 5 to other effectors, the process of which correlates with shedding of APPL1. Hence, depletion of PI3P causes a striking reversion of Rab 5 positive endosomes to the APPL stage, resulting in enhanced growth factor signaling [76]. Similar to APPL1, APPL2 is localized at the cytoplasmic and early endosomal membranes; however, the roles of APPL2 in endosomal trafficking and related signaling are largely unknown and require further investigation.
APPL in other signaling pathways
Conclusions Multifunctional adaptor proteins APPL1 and APPL2 play indispensable roles in various signaling pathways in cell proliferation, development, and apoptosis. Notably, APPL1 is not only the adiponectin receptor binding protein but also the essential protein in insulin signaling that mediates the cross talk between the insulin and adiponectin pathways. In addition, APPL1 is involved in endosome trafficking and related signaling transduction, as well as TrkA, Wnt/β-catenin, EGFR and FSHR signaling pathways in many cells and tissues (Fig. 2).
Conflict of interests
Acknowledgments This work was supported by the International Science and Technology Cooperation Program of China (2014DFG32490), the National Natural Science Foundation of China (31471131, 31571368), and the Project of Innovation-Driven Plan of Central South University (2016CX031).