Uses and abuses of macropinocytosis

Abstract

Macropinocytosis is a means by which eukaryotic cells ingest extracellular liquid and dissolved molecules. It is widely conserved amongst cells that can take on amoeboid form and, therefore, appears to be an ancient feature that can be traced back to an early stage of evolution. Recent advances have highlighted how this endocytic process can be subverted during pathology -certain cancer cells use macropinocytosis to feed on extracellular protein, and many viruses and bacteria use it to enter host cells. Prion and prion-like proteins can also spread and propagate from cell to cell through macropinocytosis. Progress is being made towards using macropinocytosis therapeutically, either to deliver drugs to or cause cell death by inducing catastrophically rapid fluid uptake. Mechanistically, the Ras signalling pathway plays a prominent and conserved activating role in amoebae and in mammals; mutant amoebae with abnormally high Ras activity resemble tumour cells in their increased capacity for growth using nutrients ingested through macropinocytosis. This Commentary takes a functional and evolutionary perspective to highlight progress in understanding and use of macropinocytosis, which is an ancient feeding process used by single-celled phagotrophs that has now been put to varied uses by metazoan cells and is abused in disease states, including infection and cancer.

ADiaphanous-related formin links Ras signaling directly to actin assembly in macropinocytosis and phagocytosis

“…Nevertheless, both processes share many similarities and components because, in both cases, the dynamic assembly of actin filaments together with myosins generates forces that drive internalization of fluid or large particles. Moreover, they are of high medical relevance because, in the immune defense, phagocytosis is a major mechanism to remove pathogens (7), whereas many cancer cells thrive by excessive macropinocytosis (3,5). Recent work with Dictyostelium showed that the nucleation-promoting factor SCAR/WAVE localizes at the very rim of macropinosomes, suggesting that the Arp2/3 complex acts as a potent nucleator of the underlying actin filament network (38).…”

“…In higher eukaryotes, as exemplified by neutrophils and macrophages, phagocytosis is a central part of the innate immune system responsible for the clearance of viral and bacterial pathogens (2), whereas the scavenging of nutrients and metabolites by macropinocytosis is considered increasingly important for tumor progression and cancer cell proliferation (3)(4)(5). Phagocytosis and macropinocytosis are actin-driven processes that entail rearrangements of the plasma membrane to engulf extracellular material, followed by delivery of the ingested material into lysosomes for extraction of nutrients (6).…”

“…This step is followed by activation of small GTPases of the Ras family, which act as master regulators of diverse downstream signaling pathways, including target of rapamycin complex 2 (14) and class-I PI3-kinases (PI3Ks) (15), albeit Dictyostelium cells use ether-linked plasmanylinositides instead of phosphatidylinositides (16). PI3K1 and PI3K2 produce patches of phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), which are linked to actin-dependent cup formation, whereas PI3K4 is required for the conversion of the cups into intracellular vesicles (15,17). The latter process is associated with rapid disassembly of the F-actin coat (18), and, consistently, a number of F-actin depolymerization factors, including coronin, actin-interacting protein (Aip1), and cofilin, were shown to participate in cup maturation and disassembly (18)(19)(20).…”

Septin Mutations in Human Cancers

“…Sustained proliferation requires a metabolic reprogramming, which includes the internalization of carbon sources and amino acids from the interstitial fluid by macropinocytosis (Bloomfield and Kay, 2016). Ras mutants have been known to upregulate macropinocytosis and septins were recently found to affect the intracellular transport of macropinosomes in a dose dependent manner (Bryant et al, 2014; Dolat and Spiliotis, 2016).…”

A Novel Role of Dickkopf-Related Protein 3 in Macropinocytosis in Human Bladder Cancer T24 Cells

“…The fluids are internalized according to the fusion of the membranous protrusions by themselves [24]. Ras, PI3K, Src and Rac1 activities have been shown to stimulate macropinocytosis [25,26,27,28,29]. Since Ras was upregulated in T24 cells in this study, it is possible that the Ras upregulation coordinately stimulated macropinocytosis with Dkk-3 and Rab5 [30].…”