Endosomal Sorting Protein SNX27 and Its Emerging Roles in Human Cancers

SIMPLE SUMMARY: The sorting nexin (SNX) family of proteins mediate the sorting and trafficking of endocytosed transmembrane proteins between the endosomal compartments, lysosome, trans-Golgi network, and plasma membrane. SNXs are characterized by the presence of a Phox domain; however, SNX27 is a unique member of this family as it contains an additional PDZ domain. Evidence suggests that SNX27, in association with the retromer complex, binds cargo via its PDZ domain and recycles them from the early endosomes to the plasma membrane, thereby escaping their lysosomal degradation. The roles of SNX27 in cancer is largely unexplored, however many of its identified cargoes have been indicated in tumorigenesis. In this review we provide a summary of the current knowledge, as supported by scientific literature and evidence, regarding the fundamental structure, biological function, and implication of SNX27 in human cancers. ABSTRACT: SNX27 belongs to the sorting nexin (SNX) family of proteins that play a critical role in protein sorting and trafficking in the endocytosis pathway. This protein family is characterized by the presence of a Phox (PX) domain; however, SNX27 is unique in containing an additional PDZ domain. Recently, SNX27 has gained popularity as an important sorting protein that is associated with the retromer complex and mediates the recycling of internalized proteins from endosomes to the plasma membrane in a PDZ domain-dependent manner. Over 100 cell surface proteins have been identified as binding partners of the SNX27–retromer complex. However, the roles and underlying mechanisms governed by SNX27 in tumorigenesis remains to be poorly understood. Many of its known binding partners include several G-protein coupled receptors, such as β2-andrenergic receptor and parathyroid hormone receptor, are associated with multiple pathways implicated in oncogenic signaling and tumorigenesis. Additionally, SNX27 mediates the recycling of GLUT1 and the activation of mTORC1, both of which can regulate intracellular energy balance and promote cell survival and proliferation under conditions of nutrient deprivation. In this review, we summarize the structure and fundamental roles of SNX proteins, with a focus on SNX27, and provide the current evidence indicating towards the role of SNX27 in human cancers. We also discuss the gap in the field and future direction of SNX27 research. Insights into the emerging roles and mechanism of SNX27 in cancers will provide better development strategies to prevent and treat tumorigenesis.