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Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.

ABSTRACT: Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.

SUBMITTER: Commisso C

PROVIDER: S-EPMC3810415 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.

Commisso Cosimo C Davidson Shawn M SM Soydaner-Azeloglu Rengin G RG Parker Seth J SJ Kamphorst Jurre J JJ Hackett Sean S Grabocka Elda E Nofal Michel M Drebin Jeffrey A JA Thompson Craig B CB Rabinowitz Joshua D JD Metallo Christian M CM Vander Heiden Matthew G MG Bar-Sagi Dafna D

Nature 20130512 7451

Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protei ...[more]

PMID: 23665962

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Project description:The tendency to reduce crude protein (CP) levels in pig diets to increase protein efficiency may increase the occurrence of damaging behaviours such as ear and tail biting, particularly for pigs kept under suboptimal health conditions. We studied, in a 2×2×2 factorial design, 576 tail-docked growing-finishing entire male pigs in 64 pens, subjected to low (LSC) vs. high sanitary conditions (HSC), and fed a normal CP (NP) vs. a low CP diet (LP, 80% of NP) ad libitum, with a basal amino acid (AA) profile or supplemented AA profile with extra threonine, tryptophan and methionine. The HSC pigs were vaccinated in the first nine weeks of life and received antibiotics at arrival at experimental farm at ten weeks, after which they were kept in a disinfected part of the farm with a strict hygiene protocol. The LSC pigs were kept on the same farm in non-disinfected pens to which manure from another pig farm was introduced fortnightly. At 15, 18, and 24 weeks of age, prevalence of tail and ear damage and of tail and ear wounds was scored. At 20 and 23 weeks of age, frequencies of biting behaviour and aggression were scored for 10×10 min per pen per week. The prevalence of ear damage during the finisher phase (47 vs. 32% of pigs, P < 0.0001) and the frequency of ear biting (1.3 vs. 1.2 times per hour, P = 0.03) were increased in LSC compared with HSC pigs. This effect on ear biting was diet dependent, however, the supplemented AA profile reduced ear biting only in LSC pigs by 18% (SC × AA profile, P < 0.01). The prevalence of tail wounds was lower for pigs in LSC (13 ± 0.02) than for pigs in HSC (0.22 ± 0.03) in the grower phase (P < 0.007). Regardless of AA profile or sanitary status, LP pigs showed more ear biting (+20%, P < 0.05), tail biting (+25%, P < 0.10), belly nosing (+152%, P < 0.01), other oral manipulation directed at pen mates (+13%, P < 0.05), and aggression (+30%, P < 0.01) than NP pigs, with no effect on ear or tail damage. In conclusion, both low sanitary conditions and a reduction of dietary protein increase the occurrence of damaging behaviours in pigs and therefore may negatively impact pig welfare. Attention should be paid to the impact of dietary nutrient composition on pig behaviour and welfare, particularly when pigs are kept under suboptimal (sanitary) conditions.

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Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.

Publications

Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.

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