Plasma from patients with fulminant hepatic failure contains a factor that stimulates the growth of adult rat hepatocytes
in primary culture. Gohda et al. (1988) purified HGF from a patient's plasma and showed that it has multiple forms with
molecular weights between 76,000 and 92,000. HGF consists of 2 chains, heavy and light, with molecular weights of
54,000-65,000 and 31,500-34,500, respectively. These chains are linked together by disulfide bonds. Miyazawa et al.
(1989) sequenced cDNAs encoding HGF. The deduced sequence of the pre-pro-protein
consisted of 728 amino acid residues. The sequence showed that the heavy and light chains are encoded by the same
mRNA and are produced from a common translation product by proteolytic processing.
Gherardi and Stoker (1990) found that HGF is structurally similar, if not identical, to scatter factor, a molecule shown to stimulate the
dissociation and scattering of epithelial cells. The sequence of HGF has about 35% identity to that of plasminogen and the putative cleavage site of HGF is identical to that of plasminogen.
NCBI Summary:
This gene encodes a protein that binds to the hepatocyte growth factor receptor to regulate cell growth, cell motility and morphogenesis in numerous cell and tissue types. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate alpha and beta chains, which form the mature heterodimer. This protein is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. This protein also plays a role in angiogenesis, tumorogenesis, and tissue regeneration. Although the encoded protein is a member of the peptidase S1 family of serine proteases, it lacks peptidase activity. Mutations in this gene are associated with nonsyndromic hearing loss. [provided by RefSeq, Nov 2015]
General function
Ligand, Growth factor
Comment
Hepatocyte growth factor (HGF) and its receptor, the Met tyrosine kinase, are
determinants of placenta, liver, and muscle development.
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.
Cellular localization
Secreted
Comment
The hepatocyte growth factor system as a regulator of female and male gonadal function. Zachow R et al. The hepatocyte growth factor (HGF) system comprises HGF, its receptor (the c-met tyrosine kinase), HGF activator (HGFA) protein, and HGFA inhibitor (HAI). The components of the HGF system have been identified in a plethora of tissues to include the ovary and testis. In its traditional context, the HGF system works via paracrine- and autocrine-mediated feedback in which HGF (of mesenchymal origin) binds and activates c-met (within epithelial cells); target cells then respond to HGF via any number of morphogenic and functional changes. The concomitant presence of HGFA and HAI suggests that HGF bioactivity can be locally modulated. A number of studies have collectively shown that the mammalian ovary and testis contain HGF, c-met, and HGFA; very little is currently known regarding HAI within the gonad. Within the ovary, HGF controls numerous key functions which collectively regulate the growth and differentiation of ovarian follicles; these include cell growth, steroidogenesis, and apoptosis within theca cells and/or granulosa cells. Comparatively, less is known about the function of HGF within the testicular Leydig and Sertoli cells, but evidence is emerging that HGF may regulate somatic cell function, including Leydig cell steroidogenesis. Changes in the cellular origin of HGF and c-met during fetal and postnatal testicular development suggest that HGF, in collaboration with other growth factors, may regulate important aspects of testicular cell morphogenesis and differentiation which enable male sexual viability. Likewise, experimental evidence showing that HGF can modulate many vital processes which enable ovarian follicle growth, differentiation, and function indicate the importance of HGF in female reproduction. This review presents what is currently known regarding the expression of the HGF system and its function within the ovary and testis.
Transcriptional characteristics of different sized follicles in relation to embryo-transferability: potential role of hepatocyte growth factor signalling. Nivet AL et al. (2016) We hypothesized that a better discrimination between follicles containing oocytes with high developmental competence and those containing oocytes with low competence, based on a combination of a follicle's size and transcriptomic signature, will provide a reliable method to predict embryonic outcome of IVF. This study provides new insights on the impact of follicular size on oocyte quality as measured by embryonic development and demonstrates that medium follicles yield a better percentage of transferable embryos. Although it is generally accepted that large ovarian follicles contain better eggs, other studies report that a better follicular size subdivision and a better characterization are needed. Individual follicles (n=136), from a total of 33 women undergoing IVF, were aspirated and categorized on the basis of their follicular liquid volume (small, medium, or large) and the embryonic outcome of the enclosed oocyte: poor or good development. Comprehensive gene expression analysis between cells from the different sized follicles was performed using microarrays and quantitative RT-PCR to find molecular markers associated with follicular maturity and oocyte developmental competence. The analysis of embryonic outcome in relation to follicular size indicates that the medium-sized follicles category yielded more transferable embryos (35%) compared to the largest follicles (30%) (NS). Gene expression analysis revealed expression markers with significant (P<0.05) discrimination between the poor development groups for all three follicle sizes, and good development medium size follicles, including upregulation of thrombomodulin, transforming growth factor, beta receptor II and chondrolecti, and those associated with hyaluronan synthesis, coagulation and hepatocyte growth factor signalling. These analyses were performed in a single cohort of patients coming from a single clinic and the biomarkers generated will require validation in different geographical and biological contexts to ensure their global applicability. Medium size follicles seem to be the optimal size for a positive embryonic outcome and are associated with competence markers that may help in understanding the ideal differentiation status during late folliculogenesis. The data discussed in this publication have been deposited in the The National Center for Biotechnology Information Gene Expression Omnibus database and are accessible through GEO Series accession number GSE52851. This study was supported by Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada (NSERC) to MA Sirard. There are no competing interests to declare.//////////////////
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.
Parrot et al reported a positive feedback loop between thecal cells and
granulosa cells that is mediated by kit ligand (KL), KGF, and HGF. Thecal cell-derived KGF and HGF can stimulate
granulosa cell-derived KL expression, and KL, in turn, can stimulate thecal cell-derived KGF and HGF
expression.
Zachow RJ, et al reported that Hepatocyte growth factor regulates ovarian theca-interstitial cell
differentiation and androgen production.
In cultured theca-interstitial cells (TIC), HGF did not alter androsterone levels in the absence of LH;
however, HGF reversibly impaired LH-dependent androsterone production by as much as 57% (IC50 =
1.5 +/- 0.01 ng/ml). LH (0.3 ng/ml) stimulated progesterone (P4) synthesis by TIC (1201 +/- 190 pg/ml)
compared to that by control cells (210 +/- 30 pg/ml). HGF stimulated basal P4 production, and
LH-dependent P4 synthesis was augmented 2.6-fold by HGF.
Parrott JA, et al. reported that mesenchymal-epithelial interactions in the ovarian follicle involve keratinocyte and hepatocyte
growth factor production by thecal cells and their action on granulosa cells. Treatment with recombinant KGF or HGF stimulated the
proliferation of bovine granulosa cells, but not thecal cells.
Lail-Trecker M, et al. reviewed the role for hepatocyte growth factor/scatter factor in regulating normal and neoplastic cells of
reproductive tissues.
Hess S, et al. reported that Hepatocyte growth factor induces rat ovarian surface epithelial cell mitosis or apoptosis depending
on the presence or absence of an extracellular matrix.
Zachow RJ,et al 2000 reported modulation of estrogen production and 17 beta-hydroxysteroid
dehydrogenase-type 1, cytochrome P450 aromatase, c-Met, and
protein kinase B alpha messenger ribonucleic acid content in
rat ovarian granulosa cells by hepatocyte growth factor and
follicle-stimulating hormone.
Expression regulated by
LH, Steroids
Comment
Liu Y et al reported the modulation of hepatocyte growth factor gene expression by
estrogen in mouse ovary.
A single injection of 17
beta-estradiol results in a dramatic and transient elevation of the levels of mouse HGF mRNA. Sequence
analysis has found that two putative estrogen responsive elements (ERE) reside at -872 in the 5'-flanking
region and at +511 in the first intron, respectively, of the mouse HGF gene. HGF gene is transcriptionally
regulated by estrogen in mouse ovary; and such regulation is mediated via a direct interaction of the
estrogen receptor complex with cis-acting ERE elements identified in the mouse HGF gene.
Osuga Yet al reported the presence of hepatocyte growth factor expression
in human ovarian follicles.
A total of 69 follicular fluid (FF) samples
were obtained during oocyte retrieval for in-vitro fertilization (IVF) from 11 patients with no apparent
endocrine disorders. The concentrations of HGF, oestradiol, progesterone, HCG and testosterone in FF
samples were measured by enzyme-linked immunosorbent assay. Transcription of HGF and its receptor,
c-met, was detected by reverse transcription-polymerase chain reaction (RT-PCR). Human FF samples
contained approximately 90-fold higher amounts of HGF (24.2 +/- 1.2 ng/ml), compared with those of
serum (0. 28 +/- 0.04 ng/ml). Concentrations of HGF in FF were positively correlated with those of
progesterone and HCG concentrations in FF. However,
HGF concentrations were not significantly correlated with oestradiol and testosterone. HGF in FF was
detected by Western blotting, as a single 90 kDa band, corresponding to a single chain form.
Additionally, mRNA for both HGF and its receptor were detected in a crude granulosa cell preparation
from the pre-ovulatory follicles.
Parrott JA, et al reported the expression and action of hepatocyte growth factor in human and bovine normal ovarian surface epithelium and ovarian cancer.
Immunolocalization of the hepatocyte growth factor (HGF) system in the rat ovary and the anti-apoptotic effect of HGF in rat ovarian granulosa cells in vitro. Uzumcu M et al. Hepatocyte growth factor (HGF) regulates granulosa cell (GC) steroidogenesis and suppresses apoptosis in non-ovarian cells. The hypothesis was thus developed that intraovarian HGF supports folliculogenesis by mediating steroidogenesis and suppressing apoptosis. To investigate the latter, the anti-apoptotic actions of HGF were tested in GCs and follicles isolated from immature rats. Results showed that HGF suppressed apoptosis in GC and follicle cultures as visualized using apoptosis indicator dye, YO-PRO-1. Immunohistochemistry was used to investigate the distribution of HGF, c-met, and HGF activator (HGFA) protein during folliculogenesis in equine chorionic gonadotropin (eCG)-primed rats. Immunoreactive HGF content was the greatest in GCs within preantral follicles. Following eCG, large antral follicles showed elevated HGF staining in theca and interstitial cells when compared with GCs. Intense c-met staining was observed in GCs within non-primed small preantral follicles; following eCG, the level of c-met was diminished in GCs, but increased within theca and interstitial cells. Theca, interstitium, and GCs in non-primed and primed ovaries contained HGFA. Following eCG, HGFA was more apparent in theca cells and the interstitium when compared to that in GCs within large antral follicles. The presence of HGF, c-met, and HGFA in preantral follicles would potentially enable the anti-apoptotic effects of HGF that were observed in vitro to occur in vivo. Advanced folliculogenesis led to a change in the cellular distribution of the HGF, c-met, and HGFA, suggesting that the ovarian HGF system is hormonally regulated in vivo.
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. Hormonal regulation of HGF was analyzed in hormone-treated theca cell cultures.
Steady-state levels of HGF mRNA in theca cells were increased by treatment with hCG (an LH agonist),
but estradiol had no effect.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment:Uehara et al. (1995) produced targeted disruption of the HGF gene in mice and found that
mice lacking the gene product fail to develop completely and die in utero. The mutation affects the embryonic liver,
which is reduced in size and shows extensive loss of parenchymal cells. In addition, development of the placenta,
particularly of trophoblast cells, is impaired. HGF/SF is thought to mediate a signal exchange between the mesenchyme
and epithelia during mouse development.