Tumorigenesis induced by coexpression of human hepatocyte growth factor and the human met protooncogene leads to high levels of expression of the ligand and receptor.
Sing RongMarianne OskarssonD FalettoIlan TsarfatyJames ResauTakehiro NakamuraE M RosenRalph F. HopkinsG F Vande Woude
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We have previously shown that, in mouse NIH/3T3 cells, it is necessary to coexpress the gene for human hepatocyte growth factor/scatter factor (HGF/SFhu) with its receptor, the human met protooncogene (methu), to activate the transforming activity of the receptor (S. Rong, M. Bodescot, D. Blair, T. Nakamura, K. Mizuno, M. Park, A. Chan, S. Aaronson, and G. F. Vande Woude, Mol. Cell. Biol., 12: 5152-5158, 1992). In this study, we report that exceptionally high levels of the ligand and its receptor are expressed in tumor cell explants after several tumor passages through nude mice. Confluent tumor cells explanted after the second passage in nude mice can express 1700 units/ml/10(6) cells/72 h of scatter activity as determined in Madin-Darby canine kidney cell scatter assays. The motogenic factor produced by these cells is easily purified by heparin-Sepharose chromatography, and the purified factor efficiently induces tyrosine phosphorylation of Methu in YaOvBix2NMA human ovarian carcinoma cells. To account for the unusually high level of HGF/SFhu and Methu expression, we propose that normal levels of Methu receptor are inefficient at transducing the signal(s) required for transformation of mouse cells. Therefore, high levels of Methu receptor are required for tumorigenesis, and corresponding high levels of the ligand are required to induce the signal. Consistent with this model, endogenous mouse scatter factor is not detected in conditioned medium from cells transformed by overexpression of the Metmu receptor.Cite
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Hepatocyte growth factor/Scatter Factor (HGF/SF) mediated stimulation of the Met receptor tyrosine kinase results in pleiotropic cellular effects including proliferation, morphogenesis, motility and invasion. In vivo, HGF/SF-Met activation has been shown to participate in tumorigenesis, angiogenesis and metastasis. Coupled with accumulating evidence that aberrant HGF/SF-Met expression is frequently observed in a variety of human tumors, often in association with progressive disease, these data present HGF/SF-Met as an attractive target for therapeutic intervention in human cancer. In this review, we will present the most compelling evidence suggesting a key role for HGF/SF-Met signaling in tumorigenesis, and discuss several possible therapeutic strategies.
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The anabolic actions of GH are mediated by the production of insulin-like growth factor I (IGF-I) from the liver and by local production of IGF-I in extrahepatic tissues. Insulin facilitates the hepatic production of IGF-I by up-regulating GH receptors (GHRs) in the liver and augmenting the IGF-I response to GH. Although GHRs have also been identified in extrahepatic tissues that produce IGF-I, the possibility that IGF-I and insulin might partake in GHR regulation, thereby modulating the effects of GH locally has not received detailed study. The aim of this study was to investigate whether IGF-I and insulin are involved in the local regulation of GHRs, using osteoblasts as a model of GH-responsive extrahepatic tissues. We have used UMR106.06, a well differentiated rat osteoblast-like cell line that expresses GHRs and exhibits a mitogenic response to GH. IGF-I and insulin (0-10 nM) increased cell number and reduced [125I]GH binding in a concentration-dependent manner, with ED50 values of 0.8 and 0.3 nM, respectively. Although IGF-I increased cell number maximally by 36.9 +/- 1.2% (mean +/- SE) above the control value and insulin by 104.8 +/- 5.7% (P < 0.001), they decreased GH binding to 47.0 +/- 9.3% (P < 0.01) and 29.8 +/- 8.7% of the control value (P < 0.001), respectively. Scatchard analysis revealed that the down-regulation of GH binding was attributed to reduced receptor numbers and not binding affinity. The effects of IGF-I and insulin at submaximal concentrations were additive, although the combined effects did not exceed the maximal effect of either growth factor alone. Addition of an anti-IGF-I receptor antibody (alpha IR3) reversed the inhibition of GH binding induced by IGF-I, but not that caused by insulin; similarly, an antiinsulin receptor antibody (29B4) attenuated the inhibitory effect of insulin only. Addition of alpha IR3 alone or an ant-IGF-I antibody (Sm1.2) decreased cell number and increased GH binding in a concentration-dependent mode. GH at 1.5 nM significant increased cell number by 19.3 +/- 2.4% above the control level (P < 0.01), an increase that was reversed by alpha IR3. GH increased GH binding by 32.4 +/- 7.2% (P < 0.05) in cells treated with alpha IR3 to remove the secondary effect of IGF-I. In summary, IGF-I and insulin acted via specific receptors to stimulate cell proliferation and down-regulate GHRs in osteoblasts. GH stimulated cell proliferation, an action mediated by local production of IGF-I, and GH enhanced its own binding. The collective data suggest the presence of a peripheral negative feedback loop that allows IGF-I to limit locally the response of extrahepatic tissues to circulating GH.
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The product of a proto-oncogene, the c-Met protein is a transmembrane receptor tyrosine kinase. Its only known ligand, hepatocyte growth factor/scatter factor, regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. Dysregulation of c-Met and hepatocyte growth factor have been observed in both clear cell and non–clear cell renal cell carcinomas (RCCs), although only papillary RCCs harbor activating mutations in the MET gene. In clear cell RCC, there is evidence of a direct link between loss of von Hippel–Lindau and up-regulation of c-Met. As in other cancers, high expression of c-Met correlates with worse outcomes in RCC. In vitro and in vivo preclinical RCC models demonstrate cancer control with small molecule and antibodies against c-Met. Given these findings, the c-Met pathway is a logical therapeutic target in RCC, and several agents are in clinical testing with early signs of efficacy.
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Abstract Zinc depletion attenuates growth and decreases circulating IGF-I. To investigate the mechanisms responsible for the IGF-I decline, we determined the effects of dietary zinc (Zn) deficiency on body and organ growth, serum IGF-I, serum GH-binding protein (GHBP), liver GH receptors and liver expression of their corresponding gene. After 1 week of adaptation to a normal zinc diet, a zinc-deficient diet (ZD; Zn, 0 p.p.m.) or a zinc-normal diet (CTR; Zn, 75 p.p.m.) was available ad libitum to 4-week-old Wistar rats for 4 weeks. Pair-fed animals (PF) received the zinc-normal diet in the same absolute amount as that consumed the day before by the ZD group. The food intake of ZD and PF rats was reduced by 32% ( P <0·001) compared with the CTR group. Zinc depletion specifically reduced body weight gain (−22%, P <0·05), serum IGF-I concentrations (−52%, P <0·001), hepatic GH receptors (−28%; P <0·05) and serum GHBP levels (−51%; P <0·05), compared with the PF group. GH concentrations were reduced in ZD animals compared with CTR rats ( P <0·01). The caloric restriction of PF animals also decreased body weight gain (−50%, P <0·001), serum IGF-I concentrations (−21%, P <0·05), liver GH receptors (−38%, P <0·001) and serum GHBP levels (−38%, P <0·01), when compared with the CTR group. Both ZD and PF groups had reduced liver IGF-I and GH receptor/GHBP mRNA levels in comparison with the CTR group ( P <0·01). However, only liver IGF-I mRNA levels were specifically reduced by zinc deficiency (ZD vs PF rats; P <0·05). Our observations suggest that beside the decline of GH secretion, decreased hepatic GH receptors and/or GHBP concentrations might be responsible for the decline of circulating IGF-I in ZD animals. Journal of Endocrinology (1995) 144, 449–456
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The effects of hCG and various pituitary hormones on type I insulin-like growth factor (IGF) receptors of purified Leydig cells of hypophysectomized rats were studied. The number of type I IGF receptors of Leydig cells obtained from hypophysectomized rats (18.0 ±1.5 fmol/106 cells) was lower than that in normal rats (54.6 ± 5.3 fmol/106 cells; P < 0.05). After a single administration of hCG (10 U, ip), specific binding of [125I]IGF-I to purified Leydig cells increased 3-fold. Scatchard analyses of the binding data suggested that increased binding was the result of an increase in receptor number, whereas binding affinity remained unaltered. Type I IGF receptor increased within 12 h and remained persistently elevated 96 h after hCG treatment. Administration of hCG (10 U, ip) daily for 5 days increased type I IGF receptor levels to 73.2 ± 8 fmol/ 106 cells (P < 0.001). FSH caused a small but significant increase in type I IGF receptors. Concomitant administration of FSH and hCG further enhanced IGF-I-binding capacity. IGF-I-binding affinity of Leydig cells treated with FSH or FSH plus LH was not significantly different from that in the control hypophysectomized rats. Daily administration of GH for 5 days also upregulated type I IGF receptors, whereas PRL had no effect. FSH, GH, and PRL administration had no effect on serum testosterone levels. Serum testosterone levels increased to 3.99 ± 0.35 ng/ml after 5 days of treatment with hCG. Concomitant administration of FSH and hCG caused a further increased in serum testosterone levels (6.13 ± 0.46 ng/ml; P < 0.01). The present study suggests that type I IGF receptors of Leydig cells can be up-regulated by LH, FSH, and GH. However, hCG/LH seems to be the most important factor in maintaining and regulating type I IGF receptors of Leydig cells. Steroidogenic and growthpromoting effects of hCG and pituitary hormones on Leydig cells may be mediated by increased type I IGF receptors. (Endocrinology123: 134–139,1988)
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Indirect evidence suggests that the serum GHbinding protein (GH-BP) is related and possibly derived from the GH-receptor. GH, through its specific receptor, is the major regulator of insulin-like growth factor I (IGF-I) synthesis. The present study was undertaken to correlate serum GH-BP activity with liver plasma membrane GH receptors and their effects on serum IGF-I concentration during spontaneous pulsation of rat (r)GH in the normal male rat and after continuous delivery of human (h)GH to hypophysectomized male rats. In the first set of experiments, 45-day-old male rats were decapitated at 15 min intervals for 4 h. Serum GH-BP levels fluctuated with a 60 min lag behind the rGH levels. IGF-I pulsated over a 3-fold concentration range. IGF-I peak levels coincided with one of the rGH peaks, but its periodicity was longer than 3 h. Taken together with our previous studies on the turnover of the GH receptors, we suggest that each GH surge results in individual pulse-related turnover wave of receptor internalization and recycling. This is accompanied by a parallel increase in serum GH-BP activity. The GH and the receptor wave are responsible for an individual secretion pulse of IFG-I. In the second set of experiments male rats were hypophysectomized at 35 days of age. Four days later osmotic minipumps were implanted for continuous delivery of hGH. After 6 days of hGH treatment the rats were killed, blood was collected for hGH, GH-BP, and IGF-I determination, and the livers were removed. Plasma membranes were prepared, and lactogenic and somatogeriic binding of [125I]hGH was evaluated. Removal of endogenous ligand was performed by exposing the membranes to 3 M MgCl2. Continuous administration of hGH induced a dose-dependent increase in liver membrane lactogenic and somatogenic binding. Parallel to that increase, serum GHBP also increased in a dose-dependent manner, and the correlation between serum GH-BP and the liver membrane receptor was significant. Furthermore, hGH induced a dose-dependent increase in IGF-I concentration. There was a close correlation between IGF-I concentration and liver somatogenic receptors. It is concluded that up-regulation of the liver membrane GH receptors is accompanied by increased GH-BP and IGF-I. In both the pulsation experiment and the continuous infusion experiment, GH-BP closely correlated with the liver membrane GH receptor. (Endocrinology126: 1914–1920,1990)
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ABSTRACT The resistance to GH and the low serum concentrations of insulin-like growth factor-I (IGF-I) that occur during fasting are accompanied by decreased GH receptors in liver homogenates. In protein restriction, however, serum IGF-I but not GH receptors are decreased, suggesting that a post-receptor defect exists. Because conclusions about the status of GH receptors during dietary manipulation are based on studies using liver homogenates, the present study was undertaken to determine whether changes in GH binding by homogenates are paralleled by changes in receptors on the cell surface considered to mediate the GH signal. Collagenase-dispersed hepatocytes or liver homogenates from 7-week-old female Wistar rats fed various diets were evaluated for changes in somatogenic receptors. Fasting for 24 h reduced significantly ( P < 0·001) the plasma concentrations of IGF-I (−31%). Likewise, GH-binding sites were decreased on hepatocytes (−55%; P <0·01) and in liver homogenates (−60%; P < 0·001) compared with controls, as was the velocity of initial binding (−77%; P <0·001). Protein restriction for 1 week decreased plasma concentrations of IGF-I (−42%; P < 0·001) but GH-binding sites were not significantly reduced on hepatocytes or in homogenates. The velocity of initial binding was also not decreased. We conclude that observations on changes in homogenate binding of bovine GH during dietary manipulation provide a reliable means of assessing changes in cell-surface GH receptors. The absence of a decline in surface binding during feeding of a low-protein diet supports the hypothesis that the decline in IGF-I during protein restriction is mediated by post-receptor events. Journal of Endocrinology (1990) 124, 159–165
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Significance Epidermal growth factor receptor (EGFR) is one of the most important membrane receptors that transduce growth signals into cells to sustain cell growth, proliferation, and survival. EGFR signal termination is initiated by EGFR internalization, followed by trafficking through endosomes, and degradation in lysosomes. How this process is regulated is still poorly understood. Here, we show that hepatocyte growth factor regulated tyrosine kinase substrate (HGS), a key protein in the EGFR trafficking pathway, is dynamically modified by a single sugar N-acetylglucosamine. This modification inhibits EGFR trafficking from endosomes to lysosomes, leading to the accumulation of EGFR and prolonged signaling. This study provides an important insight into diseases with aberrant growth factor signaling, such as cancer, obesity, and diabetes.
Internalization
ERBB3
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