The c-Met protooncogene product is a receptor-like tyrosine kinase
comprised of disulfide-linked subunits of 50 kD (alpha) and 145 kD (beta). In the fully processed c-Met product, the
alpha subunit is extracellular, and the beta subunit has extracellular, transmembrane, and tyrosine kinase domains as
well as sites of tyrosine phosphorylation. Bottaro et al. (1991) demonstrated that the beta-subunit of the c-Met
protooncogene product is the cell-surface receptor for hepatocyte growth factor.
NCBI Summary:
The proto-oncogene MET product is the hepatocyte growth factor receptor and encodes tyrosine-kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor. Various mutations in the MET gene are associated with papillary renal carcinoma. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
General function
Receptor
Comment
Taniguchi F, et al reported that hepatocyte growth factor promotes cell proliferation and inhibits progesterone secretion via PKA and MAPK pathways in a human granulosa cell line.
Hepatocyte growth factor (HGF) is a mesenchymal-derived paracrine factor that acts through a c-met receptor. The activated c-met receptor recruits various signal proteins. We used a steroidogenic human granulosa-like tumor cell line (KGN cells) to analyze the biological function of HGF in human ovary cells. First, we designed a method to analyze local production and action of HGF in the human ovary. Although c-met mRNA is expressed in KGN cells, granulosa lutein, theca, and ovarian stroma cells, we observed HGF mRNA only in theca and stroma cells. Adding HGF to the medium enhanced mitogenic activity in KGN cells. We next examined the activation of intracellular signal transduction molecules induced by HGF in KGN cells. Here, we showed that HGF activated the distinct phosphorylation of Raf-1, MEK1/2, and ERK1/2, but did not induce phosphorylation of Akt. HGF enhanced the phosphorylation of Elk-1 and c-Jun as nuclear transcription factors. U0126, a MEK1/2 inhibitor, completely abrogated the phosphorylation of ERK1/2 and the cell proliferation in response to HGF. In contrast, H-89, a protein kinase A inhibitor, further enhanced the HGF-induced phosphorylation of ERK1/2 and cell proliferation. In addition, we revealed that HGF suppressed progesterone synthesis in KGN cells. Adding HGF suppressed the forskolin-induced steroidogenic acute regulatory protein (StAR) expression, which is a key regulator in progesterone synthesis. Crosstalk signals between PKA and the mitogen-activated protein kinase (MAPK) pathway were mutually inhibitory. These results demonstrated for the first time that theca cell-derived HGF may be capable of stimulating the proliferation of granulosa cells and suppressing progesterone synthesis via an activating MAPK pathway.
The effect of hepatocyte growth factor on the initial stages of mouse follicle development. Guglielmo MC et al. Interactions between theca and granulosa cells of the follicle are critical for the coordination of ovarian follicle development. The cell-cell interactions are mediated through the local production and actions of a variety of factors. The current study is designed to investigate the expression of Hgf and its receptor, c-Met, in the mouse ovary during in vivo folliculogenesis. We found that Hgf and c-Met mRNAs were already expressed in 2-day-old ovaries, and that, while c-Met levels remained constant until 22-day-old, Hgf levels slightly but not significantly increased with age. The expression of Hgf mRNA in theca/interstitial cells was higher than in granulosa cells in 22-day-old ovaries. Immunohistochemistry analysis confirmed the expression pattern demonstrated by RT-PCR. We investigated the role of HGF at the beginning of mouse folliculogenesis and its possible interaction with Kit Ligand (KL). Interestingly, both KL and HGF were able to increase the expression of each other, creating a positive feedback loop. In the presence of HGF, we observed an increase of granulosa cell proliferation and an increase in the number of preantral and early antral follicles in ovary organ cultures. We also observed a significant increase in the diameters of follicles in individual follicle cultures. Moreover, HGF stimulated the expression of the FSH receptors (Fsh-rs), both in the whole ovary and in isolated preantral follicle cultures. Based on the data presented, we concluded that HGF exerts multiple levels of control over follicular cell functions, which collectively enable the progression of follicular development. J. Cell. Physiol. (c) 2010 Wiley-Liss, Inc.
Effects of
HGF on granulosa cell differentiated functions were examined by Parrott JA et al . Treatment with HGF reduced basal and
FSH-stimulated levels of aromatase activity in bovine and rat granulosa cells. In addition, HGF inhibited
the ability of hCG to stimulate progesterone production by granulosa cells. The inhibition of granulosa
cell steroid production by HGF is proposed to be the indirect effect of promoting cellular proliferation.
Therefore, HGF directly stimulates granulosa cell proliferation and indirectly inhibits granulosa cell
differentiated functions.
Expression regulated by
Comment
Ovarian localization
Granulosa, Theca, Follicular Fluid
Comment
The levels of hepatocyte growth factor in serum and follicular fluid and the expression of c-Met in granulosa cells in patients with polycystic ovary syndrome. Sahin N et al. OBJECTIVE: To evaluate the levels of hepatocyte growth factor (HGF) in follicular fluid (FF) and the expression of c-Met in granulosa cells (GCs) with respect to the quality of the oocyte and embryo both in patients with polycystic ovary syndrome (PCOS) and in the normal ovary during controlled ovarian hyperstimulation cycles. DESIGN: Prospective controlled study. SETTING: University hospital. PATIENT(S): Fifty-nine women undergoing IVF treatment (of whom 21 had PCOS and 38 were in the control group). INTERVENTION(S): A total of 168 FF samples were collected at the time of oocyte retrieval. The HGF levels were measured by ELISA, and the mRNA expression of c-Met in GCs was detected by real-time polymerase chain reaction. MAIN OUTCOME MEASURE(S): The predictive values of HGF levels in serum and FF and the mRNA expression of c-Met in GCs for successful fertilization and oocyte-embryo quality. RESULT(S): The levels of HGF in serum and FF and the c-Met expression in GCs were similar between the PCOS and control groups. Granulosa cells of fertilized oocytes (2PN) had a significantly higher level of c-Met expression than that in oocytes that failed to fertilize. The mean HGF level in FF was significantly higher in the grade 1 embryos than in the grades 2-4 embryos. CONCLUSION(S): This study suggests that HGF/c-Met signaling may be a crucial determinant of fertilization success.
Osuga Yet al reported the presence of hepatocyte growth factor expression
in human ovarian follicles.
Transcription of HGF and its receptor,
c-met, was detected by reverse transcription-polymerase chain reaction (RT-PCR). Messenger ribonucleic Acid expressions of hepatocyte growth factor, angiopoietins and their receptors during follicular development in gilts Shimizu T, et al .
Angiogenic factors are associated with angiogenesis during follicular development in the mammalian ovary. The aim of the present study was to determine the relationships between the vascular network and mRNA expressions of angiopoietins (Ang)-1, Ang-2 and hepatocyte growth factor (HGF), and their receptors in follicles at different developmental stages during follicular development. Ovaries in gilts were collected 72 h after equine chorionic gonadotropin (eCG, 1250 IU) treatment for histological observation of the capillary network. Granulosa cells and thecal tissues in small (<4 mm), medium (4-5 mm) or large (>5 mm) individual follicles were collected for detection of mRNA expression of HGF, Ang-1 and Ang-2 in granulosa cells, and HGF receptor (HGF-R) and Tie-2 in the theca cells by semi-quantitative RT-PCR. The number of capillaries in the thecal cell layer increased significantly in healthy follicles at all developmental stages in the eCG group compared with those in controls. The expression of Ang-1 mRNA declined in granulosa cells of medium and large follicles and the level of Ang-2 mRNA increased in granulosa cells of small follicles after eCG treatment. The ratio of Ang-2/Ang-1 increased in small, medium and large follicles from ovaries after eCG treatment, but Tie-2 mRNA expression in the theca cells did not change. The level of HGF mRNA increased in granulosa cells of small follicles after eCG treatment but HGF-R in theca cells was not increased by eCG. These data suggested that the angiopoietins might be associated with thecal angiogenesis during follicular development in eCG-treated gilts.
mRNA for both HGF and its receptor were detected in a crude granulosa cell preparation
from the pre-ovulatory follicles.
Di Renzo MF, et al. reported the overexpression of the Met/HGF receptor in ovarian cancer.
Follicle stages
Secondary, Antral, Preovulatory
Comment
Parrott JA et al reported the developmental and hormonal regulation of hepatocyte growth
factor expression and action in the bovine ovarian follicle.
Both HGF and HGFR were
detected throughout follicular development in small (< 5 mm)-, medium (5-10 mm)-, and large (> 10
mm)-sized follicles. Developmental regulation of HGF in theca cells and HGFR in granulosa
cells was analyzed in freshly isolated small-, medium-, and large-sized follicles. Observations
demonstrate that expression of HGF (in theca cells) and HGFR (in granulosa cells) was highest in
large-sized follicles.
Phenotypes
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: fertile Comment:Jeffers et al. (1997) introduced into MET cDNA mutations that had been identified in the gene in both hereditary and
sporadic forms of papillary renal carcinoma and examined the effect of each mutation in biochemical and biologic
assays. They found that the MET mutants exhibited increased levels of tyrosine phosphorylation and enhanced kinase
activity toward an exogenous substrate when compared with wildtype MET. Moreover, NIH 3T3 cells expressing
mutant MET molecules formed foci in vitro and were tumorigenic in nude mice. A strong correlation was found
between the enzymatic and biologic activity of the mutants, suggesting that tumorigenesis by MET is quantitatively
related to its level of activation