Dataset Information

EGFR-Pak Signaling Selectively Regulates Glutamine Deprivation-Induced Macropinocytosis.

ABSTRACT: Macropinocytosis has emerged as an important nutrient-scavenging pathway that supports tumor cell fitness. By internalizing extracellular protein and targeting it for lysosomal degradation, this endocytic pathway functions as an amino acid supply route, permitting tumor cell growth and survival despite the nutrient-poor conditions of the tumor microenvironment. Here, we provide evidence that a subset of pancreatic ductal adenocarcinoma (PDAC) tumors are wired to integrate contextual metabolic inputs to regulate macropinocytosis, dialing up or down this uptake pathway depending on nutrient availability. We find that regional depletion of amino acids coincides with increased levels of macropinocytosis and that the scarcity of glutamine uniquely drives this process. Mechanistically, this stimulation of macropinocytosis depends on the nutrient stress-induced potentiation of epidermal growth factor receptor signaling that, through the activation of Pak, controls the extent of macropinocytosis in these cells. These results provide a mechanistic understanding of how nutritional cues can control protein scavenging in PDAC tumors.

SUBMITTER: Lee SW

PROVIDER: S-EPMC6684838 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

EGFR-Pak Signaling Selectively Regulates Glutamine Deprivation-Induced Macropinocytosis.

Lee Szu-Wei SW Zhang Yijuan Y Jung Michael M Cruz Nathalia N Alas Basheer B Commisso Cosimo C

Developmental cell 20190627 3

Macropinocytosis has emerged as an important nutrient-scavenging pathway that supports tumor cell fitness. By internalizing extracellular protein and targeting it for lysosomal degradation, this endocytic pathway functions as an amino acid supply route, permitting tumor cell growth and survival despite the nutrient-poor conditions of the tumor microenvironment. Here, we provide evidence that a subset of pancreatic ductal adenocarcinoma (PDAC) tumors are wired to integrate contextual metabolic in ...[more]

PMID: 31257175

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Project description:Eosinophils function contributes to human allergic and autoimmune diseases, many of which currently lack curative treatment. Development of more effective treatments for eosinophil-related diseases requires expanded understanding of eosinophil signaling and biology. Cell signaling requires integration of extracellular signals with intracellular responses, and is organized in part by cholesterol rich membrane microdomains (CRMMs), commonly referred to as lipid rafts. Formation of these organizational membrane domains is in turn dependent upon the amount of available cholesterol, which can fluctuate widely with a variety of disease states. We tested the hypothesis that manipulating membrane cholesterol content in primary human peripheral blood eosinophils (PBEos) would selectively alter signaling pathways that depend upon membrane-anchored signaling proteins localized within CRMMs (e.g., mitogen activated protein kinase [MAPK] pathway), while not affecting pathways that signal through soluble proteins, like the Janus Kinase/Signal Transducer and Activator of Transcription [JAK/STAT] pathway. Cholesterol levels were increased or decreased utilizing cholesterol-chelating methyl-?-cyclodextrin (M?CD), which can either extract membrane cholesterol or add exogenous membrane cholesterol depending on whether M?CD is preloaded with cholesterol. Human PBEos were pretreated with M?CD (cholesterol removal) or M?CD+Cholesterol (M?CD+Chol; cholesterol delivery); subsequent IL-5-stimulated signaling and physiological endpoints were assessed. M?CD reduced membrane cholesterol in PBEos, and attenuated an IL-5-stimulated p38 and extracellular-regulated kinase 1/2 phosphorylation (p-p38, p-ERK1/2), and an IL-5-dependent increase in interleukin-1? (IL-1?) mRNA levels. In contrast, M?CD+Chol treatment elevated PBEos membrane cholesterol levels and basal p-p38, but did not alter IL-5-stimulated phosphorylation of ERK1/2, STAT5, or STAT3. Furthermore, M?CD+Chol pretreatment attenuated an IL-5-induced increase in cell survival at 48 hours, measured as total cellular metabolism. The reduction in cell survival following cholesterol addition despite unaltered STAT phosphorylation contradicts the current dogma in which JAK/STAT activation is sufficient to promote eosinophil survival, and suggests an additional, unidentified mechanism critically regulates IL-5-mediated human PBEos survival.

Dataset Information

EGFR-Pak Signaling Selectively Regulates Glutamine Deprivation-Induced Macropinocytosis.

Publications

EGFR-Pak Signaling Selectively Regulates Glutamine Deprivation-Induced Macropinocytosis.

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