Mathematical Modeling of Receptor-Mediated Endocytosis

Klausner, Richard D.; Renswoude, Jos van; Harford, Joe B.; Wofsy, Carla; Goldstein, Byron

doi:10.1007/978-1-4615-6904-6_9

Cited by 14 publications

(20 citation statements)

References 34 publications

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“…Internalization experiments were performed similarly to those reported for asialoglycoprotein (20). Cells were first incubated with '251-labeled EGF at 2 ng/ml for 3 h at 4°C as described above, then washed five times with cold PBS.…”

Section: Methodsmentioning

confidence: 99%

Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure.

Henderson

Baskin²,

Horbach³

et al. 1989

J. Clin. Invest.

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Exposure of the fetal rat hepatocyte to ethanol in vitro blocks epidermal growth factor (EGF)-dependent cell replication. To define possible mechanisms for this growth arrest, we determined the effects of ethanol on EGF binding and EGF receptor (EGF-R) levels. During a 24-h exposure to ethanol (1.7 mg/ml, 31 mM), cell replication was completely blocked while EGF binding per cell doubled. This effect was not specific for EGF, with variable degrees of increased binding noted for insulin, transferrin, and glucagon. Significantly increased EGF binding was seen after 6 h of ethanol exposure, and both growth arrest and enhanced EGF binding were reversed within 12 h of ethanol withdrawal. Increases in both "high" and "low" affinity sites were seen, with no changes in the apparent Kd's. Total RNA, f,-actin mRNA, and EGF-R mRNA were increased 50-70% in ethanol exposed cells. However, direct measurements of EGF-R synthesis rates by I35Sjmethionine incorporation revealed no differences between control and ethanol exposed cells. Internalization of EGF-R was significantly altered by ethanol exposure. A 2-h incubation resulted in the internalization of 57% of the ligand in control cells, while only 31% of bound EGF was internalized in the ethanol exposed cells. Thus, the enhanced EGF binding may be due to decreased efficiency of internalization.

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Section: Methodsmentioning

confidence: 99%

Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure.

Henderson

Baskin²,

Horbach³

et al. 1989

J. Clin. Invest.

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“…Receptor and transferrin cycles have been fully elucidated in many cells (Morgan, 1981(Morgan, , 1983Ciechanover et al, 1983;Dautry-Varsat et al, 1983), but the signal or signals required for internalization and recycling of the receptor-ligand complex is/are not completely known. Although there are a few controversial results on the subject (Enns et al, 1983;Klausner et al, 1984), it is generally assumed that unoccupied receptors follow the same cycle as transferrin-receptor complexes (Watts, 1985;Ajioka and Kaplan, 1986;Stein and Sussman, 1986). Until Gironks and Davis (1989), the comparative study of the endocytosis and recycling rate constants for unoccupied and occupied receptors had not been determined.…”

mentioning

confidence: 99%

“…In fact, many compounds have been proposed as modifiers of the rate constants of this process, based on their effects on external/internal receptor distribution, i.e. peptide hormones, growth factors (Davis et al, 1986;Davis and Czech, 1986;Castagnola et al, 1987), phorbol esters (May and Tyler, 1987;Sorokin et al, 1986), antibodies (McArdle and Morgan, 1983) or even transferrin itself (Klausner et al, 1983(Klausner et al, , 1984Alcantara et al, 1986;Girods and Davis, 1989). taneously in a female strain 2 guinea pig (Congdon and Lorenz, 1954), and was passaged in syngeneic animals.…”

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confidence: 99%

The influence of transferin binding to L₂C guinea pig leukemic lymphocytes on the endocytosis cycle kinetics of its receptor

Sainte‐Marie¹,

Vidal²,

Bette‐Bobillo³

et al. 1991

European Journal of Biochemistry

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The parameters regulating the internalization and recycling of transferrin-specific receptors were determined in guinea pig leukemic B lymphocytes, in the absence or presence of ligand. We show that after the cells were purified, 45-56% of the total receptors were on the cell surface. In the absence of transferrin, unoccupied receptors are quickly internalized (rate constant, 0.12 min-') whereas their recycling is much slower (rate constant, 0.026 min-'). This difference between endocytosis and recycling rates leads to a balanced receptor distribution with only 22% of the total receptors outside after incubation of the cells for 20 -30 min at 37 "C. The internalization rate of occupied receptors, measured in the presence of transferrin is faster (rate constant, 0.21 min-') than that of unoccupied receptors calculated in the absence of transferrin (0.12 min-'; see above). On the other hand, mere binding of transferrin to its receptor, without internalization, arrested by cytoplasm acidification, is sufficient to induce a large increase (by a factor of seven) in the recycling rate of unoccupied internal receptors from 0.026 min-' to 0.17 min-'. Thus, in these lymphocytes, transferrin mobilizes internal receptors by modifying the kinetic rates of internalization and recycling, leading to a new equilibrium between external and internal receptors.Iron is a critical component for animal cell proliferation (Titeux et al., 1984). It is brought into cells by transferrin, a serum protein internalized by endocytosis, after binding to specific surface receptors. Although the existence of specific receptors for transferrin was first proposed by Jandl and Katz (1963), the transferrin receptor was not purified and adequately characterized until 1979 (Seligman et al., 1979; Wdda et al., 1979; for reviews, see Trowbridge et al., 1984, and Irie and Tavassoli, 1987). Receptor and transferrin cycles have been fully elucidated in many cells (Morgan, 1981(Morgan, , 1983Ciechanover et al., 1983;Dautry-Varsat et al., 1983), but the signal or signals required for internalization and recycling of the receptor-ligand complex is/are not completely known. Although there are a few controversial results on the subject (Enns et al., 1983;Klausner et al., 1984), it is generally assumed that unoccupied receptors follow the same cycle as transferrin-receptor complexes (Watts, 1985;Ajioka and Kaplan, 1986;Stein and Sussman, 1986). Until Gironks and Davis (1989), the comparative study of the endocytosis and recycling rate constants for unoccupied and occupied receptors had not been determined. In fact, many compounds have been proposed as modifiers of the rate constants of this process, based on their effects on external/internal receptor distribution, i.e. peptide hormones, growth factors (Davis et al., 1986;Davis and Czech, 1986; Castagnola et al., 1987), phorbol esters (May and Tyler, 1987; Sorokin et al., 1986), antibodies (McArdle and Morgan, 1983) or even transferrin itself (Klausner et al., 1983(Klausner et al., , 1984 Alcantara et al., 19...

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“…cosides, rather than increase it, for it provides another way of replacing blocked pumps (Klausner et al, 1985), although the effect should be quite small in HeLa cells with their slow rate of internalisation. (b) If some of the internalised pumps are not replaced by new ones then the total density of pumps (blocked + free) on the cell surface would be reduced, and this could provide an explanation for our observation.…”

Section: Apparent Kd In Short Term Experimentsmentioning

confidence: 99%

“…One possible mechanism for this is that the inaccessible sites are internalised pumps, models for which are discussed in detail by Klausner et al (1985). In this case radioligand binding will measure AB only, not (AB + 'B) as assumed in the other models.…”

Section: Appendix 2 Models With Inaccessibilitymentioning

confidence: 99%

Discrepancy between the short and long term effects of ouabain on the sodium pumps of human cells grown in culture

Griffiths

Ogden

Cormack

et al. 1991

British J Pharmacology

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1 Human cells (HeLa) were cultured for periods up to 48 h in growth medium in the absence or presence of a range of concentrations of cardiac glycosides. In some experiments the potassium concentration of the medium was varied between 0.3 mm and the usual 5 mm. 2 For periods up to 2 h in ouabain the association and dissociation rate constants were measured and the equilibrium binding constant (KD) calculated; the apparent equilibrium binding constant (K'D) was measured after 1-2 days growth in ouabain.3 Ouabain had a K' after 2 days of 2-6 nm in 5 mM K' growth medium, a 4 fold greater blocking effect on sodium pumps after 2 days than expected from the association and dissociation rate constants measured in untreated or previously ouabain-treated cells. 4 This effect was: (a) approximately the same over a range of external potassium concentrations from 0.3 to 5 mm, although the absolute effect of ouabain over this range of potassium was much different; (b) probably not due to different isoforms of pumps in cells grown in ouabain compared to untreated cells; (c) apparently not a consequence of internalisation of pump-glycoside complexes. 5 We conclude that ouabain has only a limited access to sodium pumps in whole cells; this could be because sodium pumps cycle continuously through an inaccessible region of the plasma membrane. This effect needs to be considered both in the assessment of the magnitude of the long term effects of cardiac glycosides on cells, and in the measurement of the glycoside affinities of various isoforms of the pump.

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Mathematical Modeling of Receptor-Mediated Endocytosis

Cited by 14 publications

References 34 publications

Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure.

Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure.

The influence of transferin binding to L₂C guinea pig leukemic lymphocytes on the endocytosis cycle kinetics of its receptor

Discrepancy between the short and long term effects of ouabain on the sodium pumps of human cells grown in culture

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Mathematical Modeling of Receptor-Mediated Endocytosis

Cited by 14 publications

References 34 publications

Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure.

Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure.

The influence of transferin binding to L2C guinea pig leukemic lymphocytes on the endocytosis cycle kinetics of its receptor

Discrepancy between the short and long term effects of ouabain on the sodium pumps of human cells grown in culture

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The influence of transferin binding to L₂C guinea pig leukemic lymphocytes on the endocytosis cycle kinetics of its receptor