Uptake of Insulin and Other Ligands into Receptor-Rich Endocytic Components of Target Cells: The Endosomal Apparatus

Bergeron, John J.M.; Cruz, Jonathan C.; Khan, Masood N.; Posner, Barry I.

doi:10.1146/annurev.ph.47.030185.002123

Cited by 159 publications

(54 citation statements)

References 74 publications

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“…Subsequent investigations have implicated endosomal proteases in processing polypeptide hormones such as glucagon [3][4][5][6] and PTH [7], growth factors such as EGF [8], plant and bacterial toxins such as ricin toxin [9,10] and cholera toxin [11]. The conclusion that degradation of internalized ligands occurs or is, at least in part, initiated in endocytic vesicles is based on: (i) the high recovery of internalized ligands in purified endosomes by subcellular fractionation studies, while little association was observed with lysosomes [12]; (ii) the major accumulation of internalized hormones [3,12] and toxins [11] induced by acidotropic agents (i.e. chloroquine), while effecting a minor accumulation of these ligands in lysosomes; (iii) the extraction from endosomes of polypeptide hormone fragments of insulin [13], glucagon [3,4,6] and EGF [8] using a reverse-phase high performance liquid chromatography procedure corresponding to the in vivo sites of hormone hydrolysis; (iv) the degradation of endosomal ligands in cell-free endosomes incubated at low pH [1,2,4,8,14]; (v) the identification using morphological [15], biochemical [16] and immunological criteria [1,6,17,18] of soluble and membrane-associated endosomal hydrolases; and (vi) the demonstration using iodinated protein ligands and 0014-5793/96/$12.00 © 1996 Federation of European Biochemical Societies.…”

Section: Early Observationsmentioning

confidence: 99%

Endosomal proteolysis of internalized proteins

1996

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Endosomal proteases have been implicated in the degradation of internalized regulatory peptides involved in the control of metabolic pathways and in the processing of intracellular antigens for cytolytic immune responses. Processing in the endocytic vesicles is regulated by changes in endosomal acidity due to the presence of an ATP-dependent proton pump which modulates protease activity, protein unfolding and receptor-ligand interactions. A limited number of proteases appear to reside in endosomes which do not contain the full complement of active proteases capable of completely degrading all internalized polypeptides. Retention of some acid hydrolases in endosomes is apparently related to their association with undefined endosomal membrane receptors. The limited number of proteases and the pH gradient from neutral to acidic (pH 7 to 5) within endosomes make possible a selective and controlled processing environment in comparison to lysosomes. The full set of endo-and exopeptidases that break down proteins to amino acids are active later in the pathway in lysosomes.Key words: Endosomes; Endocytosis; Major histocompatibility complex class II; Antigen processing; Endopeptidase; Cathepsin (insulin, glucagon, epidermal growth factor (EGF), invariant chain (Ii), antibodies and vitellogenin) and activation (lysosomal hydrolases, parathyroid hormone (PTH), protein antigens and toxins) of internalized proteins. The intraendosomal cleavage of proteins following endocytosis has been studied in a large number of cells, especially hepatocytes, macrophages, B-lymphocytes, fibroblasts and oocytes. These studies have raised interesting questions regarding the extent of endosomal proteolysis in different cell types, the nature and specificity of endosomal proteases, the points in the endocytic pathway where acid hydrolases are delivered and the mechanisms by which proteases are permanently retained within endosomes. Furthermore, recent studies have demonstrated that the cysteine protease cathepsins B and H, and the aspartic protease cathepsin D play a particularly important role in endosomal proteolysis. The present review focuses on the endosomal pathways involved in the processing of polypeptide hormones and internalized antigenic proteins. Proteolytic modifications of internalized proteins in endosomes

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Section: Early Observationsmentioning

confidence: 99%

Endosomal proteolysis of internalized proteins

1996

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“…The dual role of insulin receptors in metabolic regulation and hormone degradation is based on two kinds of experimental evidence: (1) that receptor occupancy elicits biological effects (Gliemann et al, 1975) and leads to insulin degradation (Terris & Steiner, 1975) and (2) that modifications of receptors by trypsin or antibodies to insulin receptors are followed by reduced insulin action (Kono & Barham, 1971;Kahn et al, 1977) and impaired proteolysis of insulin (Terris & Steiner, 1975). Morphological and biochemical studies have provided evidence that receptor-bound insulin is translocated from the surface to the interior of the cell (for reviews see Gorden et al, 1980;Bergeron et al, 1985). Endocytosis of 1251-insulin into small cytoplasmic vesicles has been shown by electron-microscopic autoradiography (Carpentier et al, 1979) and subcellular fractionation (Suzuki & Kono, 1979).…”

Section: Vol 235mentioning

confidence: 99%

“…In spite ofthis progress the molecular mechanism of insulin action is still poorly comprehended regarding the events following the receptor binding and leading to the ultimate cellular responses. Possible mechanisms of intracellular signal transmission include changes in intracellular Ca2+ concentration, protein phosphorylation, release ofpeptide mediators, interaction with guanine nucleotide regulatory proteins and internalization of receptor-hormone complexes, but attempts to identify a second messenger in insulin action has so far been inconclusive (for reviews see Denton et al, 1981;Houslay, 1981;Houslay & Heyworth, 1983;Czech, 1984;Bergeron et al, 1985;Cheng & Lamer, 1985).…”

Section: Introductionmentioning

confidence: 99%

Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

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The insulin receptor is an integral membrane glycoprotein (Mr approximately 300,000) composed of two alpha-subunits (Mr approximately 130,000) and two beta-subunits (Mr approximately 95,000) linked by disulphide bonds. This oligomeric structure divides the receptor into two functional domains such that alpha-subunits bind insulin and beta-subunits possess tyrosine kinase activity. The amino acid sequence deduced from cDNA of the single polypeptide chain precursor of human placental insulin receptor revealed that alpha- and beta-subunits consist of 735 and 620 residues, respectively. The alpha-subunit is hydrophilic, disulphide-bonded, glycosylated and probably extracellular. The beta-subunit consists of a short extracellular region which links the alpha-subunit through disulphide bridges, a hydrophobic transmembrane region and a longer cytoplasmic region which is structurally homologous with other tyrosine kinases like the src oncogene product and EGF receptor kinases. The cellular function of insulin receptors is dual: transmembrane signalling and endocytosis of hormone. The binding of insulin to its receptor on the cell membrane induces transfer of signal from extracellular to cytoplasmic receptor domains leading to activation of cell metabolism and growth. In addition, hormone-receptor complexes are internalized leading to intracellular proteolysis of insulin, whereas receptors are recycled to the membrane. These phenomena are kinetically well-characterized, but their molecular mechanisms remain obscure. Insulin receptor in different tissues and animal species are homologous in their structure and function, but show also significant differences regarding size of alpha-subunits, binding kinetics, insulin specificity and receptor-mediated degradation. We suggest that this heterogeneity of receptors may be linked to the diversity in insulin effects on metabolism and growth in various cell types. The purified insulin receptor phosphorylates its own beta-subunit and exogenous protein and peptide substrates on tyrosine residues, a reaction which is insulin-sensitive, Mn2+-dependent and specific for ATP. Tyrosine phosphorylation of the beta-subunit activates receptor kinase activity, and dephosphorylation with alkaline phosphatase deactivates the kinase. In intact cells or impure receptor preparations, a serine kinase is also activated by insulin. The cellular role of two kinase activities associated with the insulin receptor is not known, but we propose that the tyrosine- and serine-specific kinases mediate insulin actions on metabolism and growth either through dual-signalling or sequential pathways.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Stimulation of the tyrosine kinase activity of the receptor appears to be crucial to most biological effects of insulin [4][5][6]. One of the consequences of the binding of insulin to the receptor is the stimulation of the internalization of the hormone-receptor complex [7,8]. Internalization of this complex results in the degradation of the hormone [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Brefeldin A inhibits insulin‐dependent receptor redistribution in HIRcB cells

Shome

Romero

1995

FEBS Letters

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Brefeldin A (BFA) is a potent inhibitor of intracellular vesicle traffic. We have investigated the effects of BFA on the traffic of the insulin receptor in HIRcB cells, a cell line derived from Rat-1 fibroblasts that over-expresses a normal human insulin receptor. We report here that insulin-dependent receptor redistribution is inhibited by BFA and that this drug has no effects on the insulin-independent redistribution of the receptor. Autophosphorylation of the insulin receptor and the stimulation of mitogen-activated protein kinase (MAPK) by insulin were not affected by treatment with the drug. The effects of BFA were further shown to require addition of the drug prior to the addition of insulin. BFA added 10 rain after stimulation with insulin had no effects on the redistribution of the receptor. Dose-response studies demonstrated that the effects of BFA were half-maximal at a dose of 1 ttglml and maximal at about 10 pg/ml. These findings suggest that BFA blocks an early step in the chain of events that lead to insulin receptor internalization without affecting the interactions of the receptor with insulin, the stimulation of the tyrosine kinase activity of the receptor by the hormone, or other insulin-regulated signalling pathways, such as the activation of MAPK.

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Uptake of Insulin and Other Ligands into Receptor-Rich Endocytic Components of Target Cells: The Endosomal Apparatus

Cited by 159 publications

References 74 publications

Endosomal proteolysis of internalized proteins

Endosomal proteolysis of internalized proteins

Protein kinase activity of the insulin receptor

Brefeldin A inhibits insulin‐dependent receptor redistribution in HIRcB cells

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