The role of the endosomal sorting complexes required for transport (ESCRT) in tumorigenesis

Abstract

The endosomal sorting complexes required for transport (ESCRT) are needed for three distinct cellular functions in higher eukaryotes: (i) Multivesicular body formation for the degradation of transmembrane proteins in lysosomes, (ii) midbody abscission during cytokinesis and (iii) retroviral budding. Not surprisingly, loss of ESCRT function has severe consequences, which include the failure to down-regulate growth factor receptors leading to deregulated mitogenic signaling. While it is clear that the function of the ESCRT machinery is important for embryonic development, its role in cancer is more controversial. Various experimental approaches in different model organisms arrive at partially divergent conclusions regarding the contribution of ESCRTs to tumorigenesis. Therefore the aim of this review is to provide an overview on different model systems used to study the role of the ESCRT machinery in cancer development, to highlight common grounds and present certain controversies in the field.

Oncogenic dependence of glioma cells on kish/TMEM167A regulation of vesicular trafficking

“…In GB, for example, members of the small GTPases involved in cytoskeletal dynamics and vesicle trafficking, are overexpressed and promote tumor progression (Kim et al, ; Wang & Jiang, ). Several growth factor receptors and adhesion molecules are clients of the vesicular transport, both for proper membrane localization and for degradation in the lysosomes (Mattissek & Teis, ). In fact, defective endocytic downregulation of EGFR has been associated with cancer, in particular with gliomas (Jones & Rappoport, ) (Zahonero & Sanchez‐Gomez, ).…”

S100 and annexin proteins identify cell membrane damage as the Achilles heel of metastatic cancer cells

“…31 The ESCRT machinery is involved in membrane curvature and cleavage. 86 While the role of ESCRT machinery in cancer is disputed, 87 metastatic tumor cells are long known to make use of membrane cleavage to shed their PM. 88,89 Shedding of PM by tumor cells Figure 1.…”

Endosomal sorting complexes required for ESCRTing cells toward death during neurogenesis, neurodevelopment and neurodegeneration

“…These mice die between E5.5 and E6.5 due to defects in cell proliferation and mesoderm formation . This proliferative block is caused by accumulation of p53 by deregulating MDM2 levels in these embryos . Thus again asserting the importance of the complex role the ESCRT machinery proteins play during development and neurodegeneration.…”

“…A plausible way to counterbalance receptor‐mediated signaling and hyper‐proliferation would be to increase apoptosis and cell cycle arrest, as is displayed by multiple ESCRT mutants . Depletion of TSG101 (ESCRT‐I) in mouse embryos causes accumulation of p53 protein by destabilizing MDM2 levels . Accumulation of p53 in cells is known to downregulate cell survival signaling, which could result in cell cycle arrest and ultimately cell death.…”