Stimulation of glycolysis and amino acid uptake in NRK-49F cells by transforming growth factor beta and epidermal growth factor.

Boerner, Paula; Resnick, Ross J.; Racker, Efraim

doi:10.1073/pnas.82.5.1350

Cited by 74 publications

(34 citation statements)

References 12 publications

(6 reference statements)

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“…Increased glucose uptake and metabolism in response to ligands such as EGF, IL-3, and TGF-b has been long appreciated in diverse cell types such as fibroblasts, hematopoietic progenitors, and kidney epithelial cells (Barnes and Colowick, 1976;Whetton et al, 1984;Boerner et al, 1985;Rathmell et al, 2000). Akt1 and Akt2 are both important for signaling induced by growth factor receptors, since mice deficient in both isoforms exhibit dramatic defects in more cell lineages than mice deficient in only Akt1 or Akt2 (Peng et al, 2003).…”

Section: Building a Pathway That Regulates Cellular Metabolismmentioning

confidence: 99%

Akt-dependent transformation: there is more to growth than just surviving

2005

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Section: Building a Pathway That Regulates Cellular Metabolismmentioning

confidence: 99%

Akt-dependent transformation: there is more to growth than just surviving

2005

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“…For example, platelet-derived growth factor (PDGF), insulin, insulin-like growth factor (IGF)-I, and transforming growth factor (TGF)-␤ stimulate amino acid uptake through systems A and L, and induce cell proliferation, cellular hypertrophy, and matrix synthesis. 3,[5][6][7] Angiotensin (Ang) II has similar effects on amino acid uptake by VSMCs. 8 PDGF induces gene expression of CAT, and arginine uptake through CAT is indispensable for the mitogenic activity of PDGF.…”

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confidence: 99%

Phosphatidylinositol 3-Kinase Is Required for Growth Factor–Induced Amino Acid Uptake by Vascular Smooth Muscle Cells

Higaki

Shimokado

1999

ATVB

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Abstract-Although accumulating evidence suggests that phosphatidylinositol 3-kinase (PI3K) is a common signaling molecule for growth factor-induced amino acid uptake by the cell, the role of PI3K in the uptake of different amino acids was not tested under the same conditions. In this study, we asked whether PI3K mediates platelet-derived growth factor (PDGF) -stimulated uptake of different amino acids that are taken up through 3 major amino acid transporters expressed in rat vascular smooth muscle cells and other cell types and whether PI3K mediates amino acid uptake stimulated with different growth factors and vasoactive substances. PDGF increased the uptake of [ 3 H]leucine, [3 H]proline, and [ 3 H]arginine in a dose-and time-dependent fashion. Two different PI3K inhibitors, wortmannin (100 nmol/L) and LY294002 (10 mol/L), completely inhibited the amino acid uptake stimulated by PDGF. Chinese hamster ovary cells expressing both PDGF receptor-␤ and a dominant-negative PI3K did not increase their leucine uptake when stimulated with PDGF, whereas the same cells expressing only PDGF receptor-␤ did. Transforming growth factor-␤, as well as insulin-like growth factor-I and angiotensin II, increased leucine uptake by vascular smooth muscle cells. Wortmannin and LY294002 inhibited this increase. We also found that transforming growth factor-␤ stimulated PI3K activity and the phosphorylation of Akt, a downstream signaling molecule of PI3K. A similar effect of PI3K inhibitors on amino acid uptake was observed in Swiss 3T3 cells. We conclude that PI3K mediates the uptake of different amino acids by vascular smooth muscle cells and other cell types stimulated with a variety of growth factors, including transforming growth factor-␤. Our findings suggest that PI3K may play an important role in vascular pathophysiology by regulating amino acid uptake. Key Words: phosphatidylinositol 3-kinase Ⅲ amino acid uptake Ⅲ platelet-derived growth factor Ⅲ transforming growth factor-␤

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“…The control rates of lactate production by NRK-49F cells grown in medium containing 0.1% and 10% calf serum were, respectively, 10.1 and 18. We have shown previously that the stimulation of glycolysis by TGF-f3 is inhibited by cycloheximide (11). Since in the absence of TGF-f3 there was no inhibition by methionine, it was not possible to decide whether inhibition by methionine was also sensitive to cycloheximide.…”

Section: Methodsmentioning

confidence: 99%

“…induced by TGF-j3 (11). We then examined in greater detail the effect of methionine and other amino acids on glycolysis in established tumor cell lines.…”

Section: Methodsmentioning

confidence: 99%

“…and D. Westcott). We also observed that glycolysis of confluent normal rat kidney cells (NRK-49F) was stimulated by transforming growth factor (3 6) and that the stimulation of glycolysis by TGF-,3 was inhibited in the presence of high concentrations of methionine (11). These observations prompted us to explore the effect of methionine on glycolysis of transformed cells grown in tissue culture and to ask if culture conditions influenced the response of these cells to methionine.…”

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Methionine-sensitive glycolysis in transformed cells.

Boerner¹,

Racker²

1985

Proc. Natl. Acad. Sci. U.S.A.

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Glycolysis In several tumor cell lines grown in tissue culture was inhibited by methionine. Kfrsten murine sarcoma virus-transformed rat kidney cells (K-NRK) were inhibited 60-75% by 10 mM methionine, whereas normal rat kidney (NRK-49F) cells showed little or no inhibition. Inhibition of glycolysis in K-NRK cells was manifest 2-4 hr after exposure to the amino acid. Glycolysis in a chemically transformed cell line of Madin-Darby canine kidney cells was also sensitive to methionine, but maximal inhibition (75%) required 18-24 hr of incubation with the amino acid. Under the same conditions glycolysis in the nontransformed canine cells was less than 20% inhibited by methionine. In Ehrlich ascites tumor cells grown in tissue culture, 10 mM methionine inhibited glycolysis by about 50%. Inhibition of glycolysis, even by 50 mM methionine, was rapidly reversible. Within 2 hr after removal of methionine the rate of glycolytic activity was restored to that observed in control cells. Furthermore, inhibition by methionine required a minimum level (7%) of serum in the growth medium and inhibition was not sensitive to cycloheximide. Only amino acids that are transported by system A (including the nonmetabolized analogue methylaminoisobutyric acid) specifically inhibited glycolysis in tumor cells. The only exception was phenylalanine, which was toxic to both transformed and normal cell lines.It has been known for many years that tumors have an altered methionine metabolism (1)(2)(3)(4)(5). The most striking differences are (i) the inability of many tumor cell lines to grow at low concentrations of methionine or when methionine was replaced by homocysteine, and (ii) a low level of intracellular methionine and S-adenosylmethionine. Yet these same cell lines synthesize methionine and incorporate it into proteins at rates comparable to those in normal cells. Furthermore, most transformed cell lines take up methylaminoisobutyrate (MeAIB), methionine, and other substrates via system A for amino acid transport at a considerably faster rate than their "normal" parent cells (6-8). These puzzling and paradoxical observations are unexplained. Preliminary experiments (unpublished data) showed that MeAIB, a specific substrate for system A (9), inhibited the growth of the MDCK-T1 cell line, a chemically transformed variant of Madin-Darby canine kidney (MDCK) cells (10), but did not significantly inhibit the growth of MDCK cells. A similar sensitivity to MeAIB or to methionine was observed with Ehrlich ascites tumor (EAT) cells grown in tissue culture (unpublished data of P.B. and D. Westcott). We also observed that glycolysis of confluent normal rat kidney cells (NRK-49F) was stimulated by transforming growth factor (3 6) and that the stimulation of glycolysis by TGF-,3 was inhibited in the presence of high concentrations of methionine (11). These observations prompted us to explore the effect of methionine on glycolysis of transformed cells grown in tissue culture and to ask if culture conditions influenced the response of these ce...

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Stimulation of glycolysis and amino acid uptake in NRK-49F cells by transforming growth factor beta and epidermal growth factor.

Cited by 74 publications

References 12 publications

Akt-dependent transformation: there is more to growth than just surviving

Akt-dependent transformation: there is more to growth than just surviving

Phosphatidylinositol 3-Kinase Is Required for Growth Factor–Induced Amino Acid Uptake by Vascular Smooth Muscle Cells

Methionine-sensitive glycolysis in transformed cells.

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