The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert,which is comprised of early endosomes,recycling endosomes,late endosomes,and the lysosome.In ad...The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert,which is comprised of early endosomes,recycling endosomes,late endosomes,and the lysosome.In addition,autophagosomes execute autophagy,which delivers intracellular contents to the lysosome.Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks.In the endocytic pathway,gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking,protein sorting and targeted degradation of some sorted cargo.Two opposing sorting systems are operating in these processes:the endosomal sorting complex required for transport(ESCRT)supports targeted degradation and the retromer supports retrograde retrieval of certain cargo.The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases,demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies.Here we focus on the physiological process of endosomal-lysosomal maturation,acidification and sorting systems along the endocytic pathway,and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases,especially Alzheimer’s disease(AD).展开更多
The drug gefitinib, a specific inhibitor of EGFR tyrosine kinase, has been shown to suppress the activation of EGFR signaling for survival and cell proliferation in non-small cell lung cancer cell lines. For many year...The drug gefitinib, a specific inhibitor of EGFR tyrosine kinase, has been shown to suppress the activation of EGFR signaling for survival and cell proliferation in non-small cell lung cancer cell lines. For many years, EGFR endocytosis has served as a model for investigating ligand-induced, receptor-mediated endocytosis. On EGF stimulation, EGFR is internalized and transported via clathrin-coated vesicles to early endosomes, and EGFR then recruits and phosphorylates signaling molecules, leading to the activation of downstream signaling such as MAPK/PI3K/AKT pathways-an important mechanism for regulating cell growth. Once delivered to the lysosomes, EGFR is degraded to terminate intracellular EGFR signaling via endocytosis;this process is known as receptor downregulation. Therefore, the endocytosis of EGFR is closely related with attenuation of intracellular EGFR signaling. Alternatively, EGFR is returned to cell surface from early endosomes for the continued signaling. Previous reports revealed that a competent EGF-induced endocytosis of EGFR followed by its rapid downregulation efficiently proceeds in the gefitinib-sensitive NSCLC cell lines. In contrast, gefitinib-resistant cell lines showed that EGFR endocytosis is impaired and the internalized EGFR is aggregated in the early endosomes, which is associated with the overexpressed sorting nexin 1 (SNX1), initially identified as a protein that interacts with EGFR. Thus dysregulated EGFR endocytosis is implicated in gefitinib resistance, as it leads to uncontrolled signal transduction. At present, the therapeutic relevance of EGFR endocytosis with regard to drug resistance in lung cancer has not been clarified. This review focused on the mechanism for EGFR endocytosis associated with SNX1 trafficking in gefitinib-resistant lung cancer cells.展开更多
文摘The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert,which is comprised of early endosomes,recycling endosomes,late endosomes,and the lysosome.In addition,autophagosomes execute autophagy,which delivers intracellular contents to the lysosome.Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks.In the endocytic pathway,gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking,protein sorting and targeted degradation of some sorted cargo.Two opposing sorting systems are operating in these processes:the endosomal sorting complex required for transport(ESCRT)supports targeted degradation and the retromer supports retrograde retrieval of certain cargo.The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases,demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies.Here we focus on the physiological process of endosomal-lysosomal maturation,acidification and sorting systems along the endocytic pathway,and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases,especially Alzheimer’s disease(AD).
文摘The drug gefitinib, a specific inhibitor of EGFR tyrosine kinase, has been shown to suppress the activation of EGFR signaling for survival and cell proliferation in non-small cell lung cancer cell lines. For many years, EGFR endocytosis has served as a model for investigating ligand-induced, receptor-mediated endocytosis. On EGF stimulation, EGFR is internalized and transported via clathrin-coated vesicles to early endosomes, and EGFR then recruits and phosphorylates signaling molecules, leading to the activation of downstream signaling such as MAPK/PI3K/AKT pathways-an important mechanism for regulating cell growth. Once delivered to the lysosomes, EGFR is degraded to terminate intracellular EGFR signaling via endocytosis;this process is known as receptor downregulation. Therefore, the endocytosis of EGFR is closely related with attenuation of intracellular EGFR signaling. Alternatively, EGFR is returned to cell surface from early endosomes for the continued signaling. Previous reports revealed that a competent EGF-induced endocytosis of EGFR followed by its rapid downregulation efficiently proceeds in the gefitinib-sensitive NSCLC cell lines. In contrast, gefitinib-resistant cell lines showed that EGFR endocytosis is impaired and the internalized EGFR is aggregated in the early endosomes, which is associated with the overexpressed sorting nexin 1 (SNX1), initially identified as a protein that interacts with EGFR. Thus dysregulated EGFR endocytosis is implicated in gefitinib resistance, as it leads to uncontrolled signal transduction. At present, the therapeutic relevance of EGFR endocytosis with regard to drug resistance in lung cancer has not been clarified. This review focused on the mechanism for EGFR endocytosis associated with SNX1 trafficking in gefitinib-resistant lung cancer cells.
