Insulin-induced receptor loss in cultured human lymphocytes is due to accelerated receptor degradation.

Kasuga, Masato; Kahn, C. Ronald; Hedo, J A; Obberghen, E. Van; Yamada, Kazuyo

doi:10.1073/pnas.78.11.6917

Cited by 212 publications

(117 citation statements)

References 31 publications

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“…However, these authors (Krupp and Lane, 1981 ;Standaert and Pollet, 1984) used cells cultured with insulin for a long period of time while, in the present study, this hormone was acutely administered. Therefore, although insulin exposure can be said to accelerate the degradation rate of its receptors in some cell lines (Kasuga et al, 1981 ;Knutson et al, 1983;Okabayashi et al, 1989), this does not seem to represent a general mechanism for hormone-induced down-regulation.…”

Section: Discussionmentioning

confidence: 99%

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Insulin‐Induced Proteolysis of the Insulin Receptor α‐Subunit from Rat Liver does not Occur in vivo but is Prevented in vitro by Blood Serum Proteinase Inhibitors

Sánchez-Casas

Yusta

Blázquez

1995

European Journal of Biochemistry

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Insulin binding to rat liver plasma membranes promotes the action of a plasma membrane proteinase that degrades the 135-kDa a-subunit of the insulin receptor to a 120-kDa product. It has been proposed that this proteolysis may be the initial step leading to down-regulation of the hepatic insulin receptor confirm that liver plasma membrane fractions from intact or perfused rat liver and from isolated rat hepatocytes do have a proteinase that degrades the a-subunit of the insulin receptor, whose activity increases significantly in the presence of insulin. In contrast to these in vitro results, plasma membranes and Golgi fractions isolated from liver at different times after a single intravenous injection of insulin to rats only contained intact a-subunits of the insulin receptor. Insulin administration was associated with a rapid and reversible translocation of insulin receptors from the plasma membranes to Golgi fractions but did not affect their total numbers or the receptor half-life. Incubation of rat liver plasma membranes with human, bovine or rat blood sera totally blocked a-subunit proteolysis both in the absence or presence of insulin. The three major serum proteinase inhibitors, a,-antitrypsin, a,-macroglobulin and antithrombin 111, blocked a-subunit proteolysis of the insulin receptor to a varying extent. a, -antitrypsin exhibited the highest potency, decreasing the amount of 120-kDa product by 70%. When both a,-antitrypsin and antithrombin 111 were present, inhibition increased to 85 %. Thus, the absence of proteolysis of the hepatic insulin receptor in vivo could be mostly accounted for by the antiproteolytic activity of blood serum. These findings suggest that insulin receptor a-subunit proteolysis does not represent a mechanism involved in the down-regulation of the insulin receptor in liver.

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Section: Discussionmentioning

confidence: 99%

“…The level of down-regulation in these cells is determined by the dynamic equilibrium between receptor internalization and recycling rates. However, in other cell types, downregulation has been associated with an increased rate of receptor inactivation or degradation (Kasuga et al, 1981;Knutson et al, 1983;Okabayashi et a]., 1989).…”

mentioning

confidence: 99%

Insulin‐Induced Proteolysis of the Insulin Receptor α‐Subunit from Rat Liver does not Occur in vivo but is Prevented in vitro by Blood Serum Proteinase Inhibitors

Sánchez-Casas

Yusta

Blázquez

1995

European Journal of Biochemistry

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“…For several growth factors like insulin, epidermal growth factor or platelet-derived growth factor, it has been shown that, after binding, the respective receptors are internalized and down-regulated [19][20][21][22][23]. In the present study we have investigated the fate of the hepatic IL6-receptor and its ligand after their interaction.…”

Section: Discussionmentioning

confidence: 99%

The hepatic interleukin‐6 receptor Down‐regulation of the interleukin‐6 binding subunit (gp80) by its ligand

et al. 1992

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lnterleukin-6 (IL6) exerts its action via a cell surface receptor composed or an 80 kDa IL6-binding protein (gp80) and a 130 kDa polypeptlde involved in signal transduetion (gp130). We studied the role of gpB0 in binding, internalization and down-regulation of the hepatic IL6-receptor (IL6R) by its ligand in human hepatoma cells (HepG2). Comparison of tranffected HepG2 cells overexpr~sinB gpB0 with parental cell~ indicate that gpS0 is responsible for low affinity binding (Ka = 500 pM) of IL6. Furthermore, gpS0 is rate-limiting in internalization and degradation of IL6. Internalization resulted in a rapid down-regulation (t~. ~ 15-30 rain) of I L6-binding sites at the cell surface. More than B0% of the internalized [~2~l]rhlL6 was degraded. The reappearance of IL6-binding sites at the cell surface required >8 h and was sensitive to cyeloheximide0 su$Sestin B that gpB0 is not recycled after internalization. The down-regulation of the hepatic IL6R by its tigand might play an important role as a protection a~inst overstimulation.

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“…In (Goldstein et al, 1979;Karin and Mintz, 1981). Endocytosis is also used to internalize hormnone-and growth factor-receptor complexes and to direct them to lysosomes 1865 for destruction after signal transmittance (Carpenter and Cohen, 1976;Kasuga et al, 1981). It is not clear how the yeast cell makes use of its endocytotic capacity.…”

Section: Introductionmentioning

confidence: 99%

Endocytosis in Saccharomyces cerevisiae: internalization of alpha-amylase and fluorescent dextran into cells.

Makarow¹

1985

The EMBO Journal

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'The author has published her earlier work under the name Marja Pesonen. Communicated by L.KaariainenIn the preceding paper I reported that Saccharomyces cerevisiae spheroplasts were able to internalize particulate markers, enveloped viruses, into intracellular organelles. Here the internaliation of soluble macromolecules into cells having an intact cell wall is described. a-Amylase was taken up into cells in a temperature-and concentration-dependent way. The kinetics of accumulation were linear for the firt 20-40 min at 37°C and then started to level off. Internalization of aamylase into spheroplasts displayed similar characteristics, but the accumulation rate was about four times higher than into cells. Fluorescent dextran was used to mark morphologically the compartment into which internalization occurred. This marker was accumulated into the vacuole of the cells in a time-, temperature-and concentration-dependent way. A temperature-sensitive mutant deficient in exocytosis was found to be defective in intracellular accumulation of aamylase and dextran. At the restrictive temperature, very little a-amylase accumulated into the cells and only faint staining of intracellular organelles with fluorescent dextran could be detected. At the permissive temperatures, accumulation of a-amylase and dextran into the mutant cells was comparable with accumulation into wild-type cells. I conclude that a-amylase and fluorescent dextran were internalized into S. cerevisiae cells and directed into the vacuoles.

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Insulin-induced receptor loss in cultured human lymphocytes is due to accelerated receptor degradation.

Cited by 212 publications

References 31 publications

Insulin‐Induced Proteolysis of the Insulin Receptor α‐Subunit from Rat Liver does not Occur in vivo but is Prevented in vitro by Blood Serum Proteinase Inhibitors

Insulin‐Induced Proteolysis of the Insulin Receptor α‐Subunit from Rat Liver does not Occur in vivo but is Prevented in vitro by Blood Serum Proteinase Inhibitors

The hepatic interleukin‐6 receptor Down‐regulation of the interleukin‐6 binding subunit (gp80) by its ligand

Endocytosis in Saccharomyces cerevisiae: internalization of alpha-amylase and fluorescent dextran into cells.

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