Endocytosis: a pivotal pathway for regulating metastasis

Abstract

A potentially important aspect in the regulation of tumour metastasis is endocytosis. This process consists of internalisation of cell-surface receptors via pinocytosis, phagocytosis or receptor-mediated endocytosis, the latter of which includes clathrin-, caveolae- and non-clathrin or caveolae-mediated mechanisms. Endocytosis then progresses through several intracellular compartments for sorting and routing of cargo, ending in lysosomal degradation, recycling back to the cell surface or secretion. Multiple endocytic proteins are dysregulated in cancer and regulate tumour metastasis, particularly migration and invasion. Importantly, four metastasis suppressor genes function in part by regulating endocytosis, namely, the NME, KAI, MTSS1 and KISS1 pathways. Data on metastasis suppressors identify a new point of dysregulation operative in tumour metastasis, alterations in signalling through endocytosis. This review will focus on the multicomponent process of endocytosis affecting different steps of metastasis and how metastatic-suppressor genes use endocytosis to suppress metastasis.

Fig. 1. Endosomal trafficking and metastasis suppressor genes.

A wide variety of receptors and their ligands are moved intracellularly by endocytosis. Clathrin-mediated endocytosis begins with initiation and maturation of clathrin-coated pits by AP2 complexes that are recruited to the plasma membrane and act as a principal cargo-recognition molecule. As the nascent invagination grows, AP2 and other cargo-specific adaptor proteins recruit and concentrate the cargo. AP2 complexes along with other adaptor proteins to recruit clathrin. Clathrin recruitment stabilises the curvature of the growing pit with the help of other BAR-domain-containing proteins. BAR-domain-containing proteins also recruit Dynamin to the neck of the budding vesicle, until the entire region invaginates to form a closed vesicle. Dynamin is a large GTPase, which forms a helical oligomer around the constricted neck and, upon GTP hydrolysis, mediates the fission of the vesicle to release it into the cytoplasm. Following vesicle detachment from the plasma membrane, the clathrin coat is disassembled. The released vesicle goes through a first set of fusion, leading to formation of early endosomes, where initial sorting decisions are made, and the fate of the internalised sorting proteins and lipids is decided. The RAB proteins primarily localised to the early endosome include RAB5 and RAB4, along with lesser-known RAB21 and RAB22. They regulate the motility of early endosome on actin and microtubule tracks, its homotypic fusion and specialised functions of sorting and trafficking. The internalised receptors can be sorted into recycling pathways through extensive tubulation of the early endosome membranes, wherein receptors that are sorted into the newly formed tubular membranes recycle back to the plasma membrane through recycling endosomes. Alternately, early endosome growth and maturation could lead to the trans-Golgi network (TGN) or to late endosomes. Mature late endosomes are approximately 250–1000 nm in diameter and are characterised by the generation of a RAB7 domain. Late endosomes undergo homotypic fusion reactions, grow in size and acquire more intralumenal vesicles (ILVs). ILVs containing late endosomes get enriched with RAB35 and RAB27 and their effectors that promote their fusion to plasma membrane to release exosomes (40–100 nm in diameter vesicles). Predominantly, late endosomes move to the perinuclear area of the cell where they undergo transient fusions with each other and eventually fuse with lysosomes for degradation of its content. Cellular proteins synthesised in the rough endoplasmic reticulum (ER) are constantly secreted from ER to the Golgi complex in mammals through an ER–Golgi intermediate compartment (ERGIC). Points where metastasis suppressors interact with the endocytic process are highlighted.