APPLs: More than just adiponectin receptor binding proteins.

APPLs (adaptor proteins containing the pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif) are multifunctional adaptor proteins that bind to various membrane receptors, nuclear factors and signaling proteins to regulate many biological activities and processes, such as cell proliferation, chromatin remodeling, endosomal trafficking, cell survival, cell metabolism and apoptosis. APPL1, one of the APPL isoforms, was the first identified protein and interacts directly with adiponectin receptors to mediate adiponectin signaling to enhance lipid oxidation and glucose uptake. APPLs also act on insulin signaling pathways and are important mediators of insulin sensitization. Based on recent findings, this review highlights the critical roles of APPLs, particularly APPL1 and its isoform partner APPL2, in mediating adiponectin, insulin, endosomal trafficking and other signaling pathways. A deep understanding of APPLs and their related signaling pathways may potentially lead to therapeutic and interventional treatments for obesity, diabetes, cancer and neurodegenerative diseases.