* 142409

HEPATOCYTE GROWTH FACTOR; HGF


Alternative titles; symbols

SCATTER FACTOR; SF
LUNG FIBROBLAST-DERIVED MITOGEN
HEPATOPOIETIN A


HGNC Approved Gene Symbol: HGF

Cytogenetic location: 7q21.11     Genomic coordinates (GRCh38): 7:81,699,010-81,770,047 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q21.11 Deafness, autosomal recessive 39 608265 AR 3

TEXT

Cloning and Expression

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 mass between 76 and 92 kD. HGF consists of 2 chains, heavy and light, with molecular mass of 54 to 65 kD and 31.5 and 34.5 kD, respectively. These chains are linked together by disulfide bonds. Miyazawa et al. (1989) and Nakamura 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. The difference in deduced number of amino acid residues probably indicates that HGF is distinct from hepatocyte stimulatory factor (HSF), which is the same as interferon beta-2 (147620).

Rubin et al. (1991) studied a mitogen derived from lung fibroblasts which, if not identical to HGF, is closely related to it. They showed that their human lung fibroblast-derived mitogen had a spectrum of targets including endothelial cells and melanocytes in addition to epithelial cells.

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 (173350) and the putative cleavage site of HGF is identical to that of plasminogen. A potent mitogen for hepatocytes, HGF is also known as hepatopoietin A (HBGA) (Szpirer et al., 1992).

Weidner et al. (1991) presented structural and functional evidence that human scatter factor (SF) and human HGF are identical proteins encoded by a single gene. Lung fibroblast-derived mitogen is also coded by the same gene. The HGF cellular receptor gene, the MET oncogene (164860), is located on 7q with the HGF gene. Thus, cells with polysomy of chromosome 7 may simultaneously overproduce both the factor and its receptor and acquire invasive properties through an autocrine mechanism. An increase in the copy number of chromosome 7 is one of the most common chromosome abnormalities observed in human malignant gliomas (137800).

Schultz et al. (2009) determined that HGF shares 88% identity with its mouse homolog. The authors stated that there are multiple isoforms of HGF. HGF isoform-1 encodes a preprotein that is cleaved into alpha and beta chains. The alpha chain is composed of a hairpin loop follow by 4 N-terminal kringle domains, and the beta chain has homology to trypsin-like serine proteases but has no catalytic function. HGF isoform-2 encodes only 2 kringle domains, and HGF isoform-3 and isoform-4 are similar to 1 and 2, respectively, differing only in the use of alternate exon 5b splice acceptor site. Isoform-5 encodes only 1 kringle domain and utilizes the exon 5a acceptor site. Schultz et al. (2009) identified 2 additional short isoforms of HGF including exons 1 to 4 and a 3-prime untranslated region transcribed from intron 4.


Mapping

Fukuyama et al. (1991) assigned the HGF gene to chromosome 7 by spot-blot hybridization using flow-sorted chromosomes. By in situ hybridization, the gene was further localized to the centromeric region of band 7q21. The location can be stated to be 7q21.1. By in situ hybridization, Weidner et al. (1991) mapped the gene to 7q11.2-q21. Zarnegar et al. (1992) assigned the gene to chromosome 7 by Southern analysis of human/hamster somatic cell hybrids. By the analysis of somatic cell hybrid DNA, Szpirer et al. (1992) assigned the HGF gene to human chromosome 7 and rat chromosome 4. Saccone et al. (1992) used a nonisotopic in situ hybridization method to map HGF to 7q21.1.


Gene Function

Kilby et al. (1996) found that the protein and mRNA for both hepatocyte growth factor and its receptor (MET) are present in third trimester placentas, suggesting that HGF serves as a paracrine mediator to control placental development and growth.

B cells develop in the bone marrow from progenitor cells that have been designated pre-pro-B cells, pro-B cells (no immunoglobulin, or Ig, chains chosen), pre-B cells (which have selected a heavy chain but not a light chain), and finally B cells (which express both heavy and light chains of the Ig molecule). Differentiation of pre-pro-B cells to pro-B cells requires signaling through IL7 receptor (IL7R; 146661) mediated by the pre-pro-B cell growth-stimulating factor (PPBSF), which consists of IL7 (146660) and a 30-kD protein cofactor. By amino acid sequencing and RT-PCR analysis, Lai and Goldschneider (2001) determined that the PPBSF cofactor is the 30-kD beta chain of HGF (HGFB) produced independently of the 60-kD alpha chain of HGF. Formation of an IL7-HGFB heterodimer requires the presence of heparin sulfate. Functional analysis indicated that either IL7 or HGFB can maintain the viability of pre-pro-B cells, but only the heterodimer can stimulate their proliferation and differentiation into pro-B cells. Lai and Goldschneider (2001) concluded that PPBSF is a novel form of cytokine, a hybrid cytokine, consisting of the bioactive components of 2 unrelated cytokines. They proposed that through its heparin-binding and mitogenic properties, HGFB enables IL7 to participate in cognate interactions at the stromal cell surface and transduce signals effectively at low levels of IL7R.

To explore the role of sinusoidal endothelial cells in the adult liver, LeCouter et al. (2003) studied the effects of VEGF receptor (VEGFR1; 165070) activation on mouse hepatocyte growth. Delivery of VEGFA (192240) increased liver mass in mice but did not stimulate growth of hepatocytes in vitro unless liver sinusoidal endothelial cells were also present in the culture. HGF was identified as one of the liver sinusoidal endothelial cell-derived paracrine mediators promoting hepatocyte growth. Selective activation of VEGFR1 stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin.

Carrolo et al. (2003) demonstrated that wounding of hepatocytes by migration of sporozoites of the rodent malarial parasite Plasmodium berghei induced secretion of HGF, which rendered hepatocytes susceptible to infection. Infection depended on activation of the HGF receptor, MET (164860), by secreted HGF. The malaria parasite exploited MET not as a primary binding site, but as a mediator of signals that made host cells susceptible to infection. HGF/MET signaling induced rearrangements of the host-cell actin cytoskeleton that were required for early development of parasites within hepatocytes.

Kaushansky and Kappe (2011) sought to determine if the mechanism of HGF induction by P. berghei described by Carrolo et al. (2003) applied to other Plasmodium species. They were able to reproduce the findings with P. berghei, but not with another rodent malaria parasite, P. yoelii, or with the human parasite, P. falciparum. Rodriguez and Mota (2011) concurred with the findings, but noted that the different rodent models remain useful in understanding the mechanisms underlying Plasmodium infection and contribute to future strategies to combat malaria.

NK4, which consists of the N-terminal hairpin domain and 4 kringle domains of the alpha chain of HGF, acts as an HGF antagonist and angiogenesis inhibitor. Wen et al. (2007) found that treating mice repeatedly with human NK4 gene therapy inhibited colon cancer growth and metastasis.

Straussman et al. (2012) developed a coculture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. They found that stroma-mediated resistance is common, particularly to targeted agents. Proteomic analysis showed that stromal cell secretion of HGF resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signaling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF (164757)-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines.

Wilson et al. (2012) independently found that HGF confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells, and generalized that there is extensive redundancy of receptor tyrosine kinase (RTK)-transduced signaling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.


Molecular Genetics

Ma et al. (2009) identified a cis-acting DNA element located 750 bp upstream from the transcription start site of the human HGF promoter that acts as a transcriptional repressor. The promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which the authors termed 'deoxyadenosine tract element' (DATE). A scan of human breast cancer (114480) cells overexpressing HGF identified somatic truncating mutations within the DATE region of the HGF gene that modulated chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter. Truncating DATE variants with 25 or fewer deoxyadenosines were found in breast cancer tumors of 51% of African Americans and 15% of individuals of mixed European descent. Notably, breast cancer patients with the truncated DATE variant were substantially younger than those with a wildtype genotype. Truncated DATE also occurred in normal individuals, indicating that it is polymorphic and may be a modifier of predisposition to disease.

Autosomal Recessive Deafness 39

In Pakistani and Indian families with autosomal recessive profound prelingual deafness mapping to chromosome 7q11.22-q21.12 (DFNB39; 608265), Schultz et al. (2009) identified 3 mutations in the HGF gene: a synonymous substitution in exon 5 (142409.0001) and a 3-bp and a 10-bp deletion in intron 4 (142409.0002 and 142409.0003, respectively). The synonymous substitution was shown to affect splicing in vitro, and the 2 deletions occur in a highly conserved sequence that is part of the 3-prime untranslated region of a previously undescribed short isoform of HGF.


Animal Model

Schmidt et al. (1995) and 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. Both the HGF gene and the gene for its receptor, the product of the MET protooncogene (164860), are expressed in many tissues during embryonic development and in the adult. The findings of these studies indicate that HGF/SF is an essential mediator of allantoic mesenchyme-trophoblastic epithelia interaction required for placental organogenesis.

Maina et al. (1996) reported that HGF and MET are determinants of placenta, liver, and muscle development. They demonstrated that Met function in vivo requires signaling via 2 C-terminal tyrosines. For this purpose they introduced point mutations into the multifunctional docking sites of the mouse Met receptor (Y(1349)VHVNATY(1356)VNV) using the 'knock in' approach described by Hanks et al. (1995). These 2 phosphotyrosines in the C-terminal tail act as multifunctional docking sites for SH2-containing effectors. Maina et al. (1996) demonstrated that mutation of both of these residues in the mouse genome caused embryonal death with placental liver and limb muscle defects, mimicking the phenotype of Met-null mutants. They noted that the Y(1356)VNV motif in particular binds Grb2 (108355) and links the receptor with Ras (see 190020). They disrupted the consensus sequences for Grb2 binding and reported that development proceeded to term without affecting placenta and liver but caused a striking reduction in limb muscle coupled to a generalized deficit of secondary fibers. Maina et al. (1996) concluded that these data showed tissue-specific differences in MET signaling and revealed a novel role for HGF in late myogenesis.

Murine melanocytes ordinarily are confined to hair follicles. The skin of transgenic mice in which a metallothionein gene promoter forces the overexpression of Hgf/Sf has melanocytes in the dermis, epidermis, and dermal-ectodermal junction, and is thus more akin to human skin. Noonan et al. (2001) subjected albino Hgf/Sf transgenic mice and wildtype littermates to erythemal ultraviolet irradiation at 3.5 days of age, 6 weeks of age, or both. A single neonatal dose, which was 30-fold lower than the total ultraviolet dose administered previously to adult mice, was sufficient to induce melanoma in Hgf/Sf-transgenic mice after a relatively short latent period and with high cumulative incidence. This neonatal dose roughly corresponds to a sunburning dose of natural sunlight at midlatitudes in midsummer. Melanoma development in the transgenic mice after ultraviolet irradiation at both 3.5 days and 6 weeks was indistinguishable from that seen after only a single exposure at 3.5 days, whereas a similar dose at 6 weeks was not tumorigenic. However, the second exposure to ultraviolet light increased the multiplicity of melanocytic lesions as well as the incidence of nonmelanocytic tumors, including squamous cell carcinoma and sarcoma. Melanomas were not seen in either nontransgenic or untreated transgenic mice during the course of the experiment.

Using in situ hybridization and immunoblotting, Powell et al. (2001) detected expression of Hgf and Met in the cerebral wall and ganglionic eminence of the developing mouse forebrain. Using conditioned media and forebrain explants for scatter assays, Powell et al. (2001) concluded that the forebrain exhibits regionally specific motogenic activity attributable to Hgf. Powell et al. (2001) hypothesized that HGF is a key molecular constituent in guiding interneuron migration from the ganglionic eminence to the cerebral cortex.

Jin et al. (2004) found that overexpression of HGF in the retinal pigment epithelium (RPE) in rabbits induced chronic serous retinal detachment with subretinal proliferation of RPE.

Using lentiviral vector technology to deliver uncleavable Hgf to mice, Mazzone et al. (2004) found that uncleavable Hgf inhibited both protease-mediated pro-Hgf conversion and active Hgf-induced Met receptor activation; that local expression of uncleavable Hgf in tumors suppressed tumor growth, impaired tumor angiogenesis, and prevented metastatic dissemination; and that systemic expression of uncleavable Hgf dramatically inhibited the growth of transplanted tumors and abolished the formation of spontaneous metastases without perturbing vital physiologic functions. Mazzone et al. (2004) concluded that proteolytic activation of pro-HGF is a limiting step in tumor progression.

Schultz et al. (2009) generated mice with a conditional knockout of Hgf in the inner ear and observed morphologic defects of the inner ear not seen in littermate controls, including a disorganized tectorial membrane onto which the Reissner membrane was collapsed, thin and flattened stria vascularis with occasional clumps of cellular proliferation, hypoplastic spiral ganglion, and outer hair cell (OHC) degeneration throughout the organ of Corti. MH19-Hgf transgenic mice overexpressing Hgf by 3- to 50-fold had an average 60-dB greater auditory-evoked brainstem response (ABR) threshold compared to littermate controls, consistent with the loss of cochlear amplification due to OHC degeneration. Inspection of the organ of Corti confirmed OHC degeneration in a spatial gradient, from complete OHC loss at the base to near-normal complement of OHCs at the apex; inner hair cells appeared normal.


ALLELIC VARIANTS ( 3 Selected Examples):

.0001 DEAFNESS, AUTOSOMAL RECESSIVE 39

HGF, SER165SER
  
RCV000016089

In 3 affected members of a consanguineous Pakistani family ('family PKDF210') segregating profound prelingual deafness (DFNB39; 608265), Schultz et al. (2009) identified homozygosity for a 495G-A transition in exon 5 of the HGF gene, resulting in a synonymous ser165-to-ser (S165S) substitution. The transition occurs 13 nucleotides into exon 5 relative to the exon 5a splice acceptor site of HGF isoform-1, but at the -3 position (483-3G-A) relative to the exon 5b splice acceptor site of HGF isoform-3, and is predicted to alter the relative strengths of the 2 splice acceptor sites. In vitro assay using a construct with the 495G-A transition produced clones with the exon 5b splice acceptor site exclusively. The 495G-A transition was not found in 1,040 chromosomes from Pakistani, Caucasian, and Human Diversity Panel controls.


.0002 DEAFNESS, AUTOSOMAL RECESSIVE 39

HGF, 3-BP DEL, 1986TGA
  
RCV000016090

In affected members of 36 Pakistani and 2 Indian families segregating recessive profound prelingual deafness (DFNB39; 608265), Schultz et al. (2009) identified homozygosity for a 3-bp deletion (1986delTGA) in intron 4 of the HGF gene, within a highly conserved sequence that is part of the 3-prime untranslated region of a previously undescribed short form of HGF, predicted to encode 24 additional amino acids before encountering a stop codon. Heterozygosity for the 3-bp deletion was found in 2 of 429 Pakistani controls, but the mutation was not found in 415 Caucasian, Indian, or Human Diversity Panel controls.


.0003 DEAFNESS, AUTOSOMAL RECESSIVE 39

HGF, 10-BP DEL, NT482+1991
   RCV000016091

In affected members of 2 Pakistani families ('PKDF601' and 'DEM4472') segregating recessive profound prelingual deafness (DFNB39; 608265), Schultz et al. (2009) identified homozygosity for a 10-bp deletion (482+1991delGATGATGAAA) in intron 4 of the HGF gene, within a highly conserved sequence that is part of the 3-prime untranslated region of a previously undescribed short form of HGF, predicted to encode 24 additional amino acids before encountering a stop codon. The 10-bp deletion was not found in 1,688 control chromosomes.


REFERENCES

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  11. Ma, J., DeFrances, M. C., Zou, C., Johnson, C., Ferrell, R., Zarnegar, R. Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer. J. Clin. Invest. 119: 478-491, 2009. [PubMed: 19188684, images, related citations] [Full Text]

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  13. Mazzone, M., Basilico, C., Cavassa, S., Pennacchietti, S., Risio, M., Naldini, L., Comoglio, P. M., Michieli, P. An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice. J. Clin. Invest. 114: 1418-1432, 2004. [PubMed: 15545993, images, related citations] [Full Text]

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  18. Rodriguez, A., Mota, M. M. Reply to Kaushansky and Kappe. (Letter) Nature Med. 17: 1181 only, 2011.

  19. Rubin, J. S., Chan, A. M.-L., Bottaro, D. P., Burgess, W. H., Taylor, W. G., Cech, A. C., Hirschfield, D. W., Wong, J., Miki, T., Finch, P. W., Aaronson, S. A. A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc. Nat. Acad. Sci. 88: 415-419, 1991. [PubMed: 1824873, related citations] [Full Text]

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  22. Schultz, J. M., Khan, S. N., Ahmed, Z. M., Riazuddin, S., Waryah, A. M., Chhatre, D., Starost, M. F., Ploplis, B., Buckley, S., Velasquez, D., Kabra, M., Lee, K., and 11 others. Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am. J. Hum. Genet. 85: 25-39, 2009. [PubMed: 19576567, images, related citations] [Full Text]

  23. Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., Cooper, Z. A., Chapman, P. B., Solit, D. B., Ribas, A., Lo, R. S., Flaherty, K. T., Ogino, S., Wargo, J. A., Golub, T. R. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487: 500-504, 2012. [PubMed: 22763439, images, related citations] [Full Text]

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  27. Wen, J., Matsumoto, K., Taniura, N., Tomioka, D., Nakamura, T. Inhibition of colon cancer growth and metastasis by NK4 gene repetitive delivery in mice. Biochem. Biophys. Res. Commun. 358: 117-123, 2007. [PubMed: 17467663, related citations] [Full Text]

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  29. Zarnegar, R., Petersen, B., DeFrances, M. C., Michalopoulos, G. Localization of hepatocyte growth factor (HGF) gene on human chromosome 7. Genomics 12: 147-150, 1992. [PubMed: 1531136, related citations] [Full Text]


Ada Hamosh - updated : 9/18/2012
Paul J. Converse - updated : 10/20/2011
Paul J. Converse - updated : 10/28/2010
Cassandra L. Kniffin - updated : 9/15/2009
Marla J. F. O'Neill - updated : 7/30/2009
Marla J. F. O'Neill - updated : 1/19/2005
Jane Kelly - updated : 7/26/2004
Ada Hamosh - updated : 10/29/2003
Ada Hamosh - updated : 2/21/2003
Dawn Watkins-Chow - updated : 6/12/2002
Paul J. Converse - updated : 1/28/2002
Ada Hamosh - updated : 9/21/2001
Moyra Smith - updated : 12/13/1996
Creation Date:
Victor A. McKusick : 12/29/1989
carol : 02/16/2015
alopez : 9/19/2012
terry : 9/18/2012
mgross : 10/20/2011
mgross : 10/20/2011
terry : 10/20/2011
mgross : 10/28/2010
wwang : 9/24/2009
ckniffin : 9/15/2009
wwang : 8/12/2009
wwang : 8/12/2009
terry : 7/30/2009
carol : 1/20/2005
terry : 1/19/2005
tkritzer : 7/27/2004
terry : 7/26/2004
alopez : 11/7/2003
alopez : 10/29/2003
terry : 10/29/2003
alopez : 2/25/2003
terry : 2/21/2003
cwells : 6/12/2002
mgross : 1/28/2002
alopez : 9/24/2001
terry : 9/21/2001
carol : 9/20/1999
mark : 12/13/1996
jenny : 12/12/1996
mark : 12/9/1996
terry : 11/19/1996
terry : 3/7/1995
pfoster : 4/20/1994
carol : 6/30/1992
carol : 6/26/1992
supermim : 3/16/1992
carol : 2/22/1992

* 142409

HEPATOCYTE GROWTH FACTOR; HGF


Alternative titles; symbols

SCATTER FACTOR; SF
LUNG FIBROBLAST-DERIVED MITOGEN
HEPATOPOIETIN A


HGNC Approved Gene Symbol: HGF

Cytogenetic location: 7q21.11     Genomic coordinates (GRCh38): 7:81,699,010-81,770,047 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q21.11 Deafness, autosomal recessive 39 608265 Autosomal recessive 3

TEXT

Cloning and Expression

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 mass between 76 and 92 kD. HGF consists of 2 chains, heavy and light, with molecular mass of 54 to 65 kD and 31.5 and 34.5 kD, respectively. These chains are linked together by disulfide bonds. Miyazawa et al. (1989) and Nakamura 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. The difference in deduced number of amino acid residues probably indicates that HGF is distinct from hepatocyte stimulatory factor (HSF), which is the same as interferon beta-2 (147620).

Rubin et al. (1991) studied a mitogen derived from lung fibroblasts which, if not identical to HGF, is closely related to it. They showed that their human lung fibroblast-derived mitogen had a spectrum of targets including endothelial cells and melanocytes in addition to epithelial cells.

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 (173350) and the putative cleavage site of HGF is identical to that of plasminogen. A potent mitogen for hepatocytes, HGF is also known as hepatopoietin A (HBGA) (Szpirer et al., 1992).

Weidner et al. (1991) presented structural and functional evidence that human scatter factor (SF) and human HGF are identical proteins encoded by a single gene. Lung fibroblast-derived mitogen is also coded by the same gene. The HGF cellular receptor gene, the MET oncogene (164860), is located on 7q with the HGF gene. Thus, cells with polysomy of chromosome 7 may simultaneously overproduce both the factor and its receptor and acquire invasive properties through an autocrine mechanism. An increase in the copy number of chromosome 7 is one of the most common chromosome abnormalities observed in human malignant gliomas (137800).

Schultz et al. (2009) determined that HGF shares 88% identity with its mouse homolog. The authors stated that there are multiple isoforms of HGF. HGF isoform-1 encodes a preprotein that is cleaved into alpha and beta chains. The alpha chain is composed of a hairpin loop follow by 4 N-terminal kringle domains, and the beta chain has homology to trypsin-like serine proteases but has no catalytic function. HGF isoform-2 encodes only 2 kringle domains, and HGF isoform-3 and isoform-4 are similar to 1 and 2, respectively, differing only in the use of alternate exon 5b splice acceptor site. Isoform-5 encodes only 1 kringle domain and utilizes the exon 5a acceptor site. Schultz et al. (2009) identified 2 additional short isoforms of HGF including exons 1 to 4 and a 3-prime untranslated region transcribed from intron 4.


Mapping

Fukuyama et al. (1991) assigned the HGF gene to chromosome 7 by spot-blot hybridization using flow-sorted chromosomes. By in situ hybridization, the gene was further localized to the centromeric region of band 7q21. The location can be stated to be 7q21.1. By in situ hybridization, Weidner et al. (1991) mapped the gene to 7q11.2-q21. Zarnegar et al. (1992) assigned the gene to chromosome 7 by Southern analysis of human/hamster somatic cell hybrids. By the analysis of somatic cell hybrid DNA, Szpirer et al. (1992) assigned the HGF gene to human chromosome 7 and rat chromosome 4. Saccone et al. (1992) used a nonisotopic in situ hybridization method to map HGF to 7q21.1.


Gene Function

Kilby et al. (1996) found that the protein and mRNA for both hepatocyte growth factor and its receptor (MET) are present in third trimester placentas, suggesting that HGF serves as a paracrine mediator to control placental development and growth.

B cells develop in the bone marrow from progenitor cells that have been designated pre-pro-B cells, pro-B cells (no immunoglobulin, or Ig, chains chosen), pre-B cells (which have selected a heavy chain but not a light chain), and finally B cells (which express both heavy and light chains of the Ig molecule). Differentiation of pre-pro-B cells to pro-B cells requires signaling through IL7 receptor (IL7R; 146661) mediated by the pre-pro-B cell growth-stimulating factor (PPBSF), which consists of IL7 (146660) and a 30-kD protein cofactor. By amino acid sequencing and RT-PCR analysis, Lai and Goldschneider (2001) determined that the PPBSF cofactor is the 30-kD beta chain of HGF (HGFB) produced independently of the 60-kD alpha chain of HGF. Formation of an IL7-HGFB heterodimer requires the presence of heparin sulfate. Functional analysis indicated that either IL7 or HGFB can maintain the viability of pre-pro-B cells, but only the heterodimer can stimulate their proliferation and differentiation into pro-B cells. Lai and Goldschneider (2001) concluded that PPBSF is a novel form of cytokine, a hybrid cytokine, consisting of the bioactive components of 2 unrelated cytokines. They proposed that through its heparin-binding and mitogenic properties, HGFB enables IL7 to participate in cognate interactions at the stromal cell surface and transduce signals effectively at low levels of IL7R.

To explore the role of sinusoidal endothelial cells in the adult liver, LeCouter et al. (2003) studied the effects of VEGF receptor (VEGFR1; 165070) activation on mouse hepatocyte growth. Delivery of VEGFA (192240) increased liver mass in mice but did not stimulate growth of hepatocytes in vitro unless liver sinusoidal endothelial cells were also present in the culture. HGF was identified as one of the liver sinusoidal endothelial cell-derived paracrine mediators promoting hepatocyte growth. Selective activation of VEGFR1 stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin.

Carrolo et al. (2003) demonstrated that wounding of hepatocytes by migration of sporozoites of the rodent malarial parasite Plasmodium berghei induced secretion of HGF, which rendered hepatocytes susceptible to infection. Infection depended on activation of the HGF receptor, MET (164860), by secreted HGF. The malaria parasite exploited MET not as a primary binding site, but as a mediator of signals that made host cells susceptible to infection. HGF/MET signaling induced rearrangements of the host-cell actin cytoskeleton that were required for early development of parasites within hepatocytes.

Kaushansky and Kappe (2011) sought to determine if the mechanism of HGF induction by P. berghei described by Carrolo et al. (2003) applied to other Plasmodium species. They were able to reproduce the findings with P. berghei, but not with another rodent malaria parasite, P. yoelii, or with the human parasite, P. falciparum. Rodriguez and Mota (2011) concurred with the findings, but noted that the different rodent models remain useful in understanding the mechanisms underlying Plasmodium infection and contribute to future strategies to combat malaria.

NK4, which consists of the N-terminal hairpin domain and 4 kringle domains of the alpha chain of HGF, acts as an HGF antagonist and angiogenesis inhibitor. Wen et al. (2007) found that treating mice repeatedly with human NK4 gene therapy inhibited colon cancer growth and metastasis.

Straussman et al. (2012) developed a coculture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. They found that stroma-mediated resistance is common, particularly to targeted agents. Proteomic analysis showed that stromal cell secretion of HGF resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signaling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF (164757)-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines.

Wilson et al. (2012) independently found that HGF confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells, and generalized that there is extensive redundancy of receptor tyrosine kinase (RTK)-transduced signaling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.


Molecular Genetics

Ma et al. (2009) identified a cis-acting DNA element located 750 bp upstream from the transcription start site of the human HGF promoter that acts as a transcriptional repressor. The promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which the authors termed 'deoxyadenosine tract element' (DATE). A scan of human breast cancer (114480) cells overexpressing HGF identified somatic truncating mutations within the DATE region of the HGF gene that modulated chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter. Truncating DATE variants with 25 or fewer deoxyadenosines were found in breast cancer tumors of 51% of African Americans and 15% of individuals of mixed European descent. Notably, breast cancer patients with the truncated DATE variant were substantially younger than those with a wildtype genotype. Truncated DATE also occurred in normal individuals, indicating that it is polymorphic and may be a modifier of predisposition to disease.

Autosomal Recessive Deafness 39

In Pakistani and Indian families with autosomal recessive profound prelingual deafness mapping to chromosome 7q11.22-q21.12 (DFNB39; 608265), Schultz et al. (2009) identified 3 mutations in the HGF gene: a synonymous substitution in exon 5 (142409.0001) and a 3-bp and a 10-bp deletion in intron 4 (142409.0002 and 142409.0003, respectively). The synonymous substitution was shown to affect splicing in vitro, and the 2 deletions occur in a highly conserved sequence that is part of the 3-prime untranslated region of a previously undescribed short isoform of HGF.


Animal Model

Schmidt et al. (1995) and 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. Both the HGF gene and the gene for its receptor, the product of the MET protooncogene (164860), are expressed in many tissues during embryonic development and in the adult. The findings of these studies indicate that HGF/SF is an essential mediator of allantoic mesenchyme-trophoblastic epithelia interaction required for placental organogenesis.

Maina et al. (1996) reported that HGF and MET are determinants of placenta, liver, and muscle development. They demonstrated that Met function in vivo requires signaling via 2 C-terminal tyrosines. For this purpose they introduced point mutations into the multifunctional docking sites of the mouse Met receptor (Y(1349)VHVNATY(1356)VNV) using the 'knock in' approach described by Hanks et al. (1995). These 2 phosphotyrosines in the C-terminal tail act as multifunctional docking sites for SH2-containing effectors. Maina et al. (1996) demonstrated that mutation of both of these residues in the mouse genome caused embryonal death with placental liver and limb muscle defects, mimicking the phenotype of Met-null mutants. They noted that the Y(1356)VNV motif in particular binds Grb2 (108355) and links the receptor with Ras (see 190020). They disrupted the consensus sequences for Grb2 binding and reported that development proceeded to term without affecting placenta and liver but caused a striking reduction in limb muscle coupled to a generalized deficit of secondary fibers. Maina et al. (1996) concluded that these data showed tissue-specific differences in MET signaling and revealed a novel role for HGF in late myogenesis.

Murine melanocytes ordinarily are confined to hair follicles. The skin of transgenic mice in which a metallothionein gene promoter forces the overexpression of Hgf/Sf has melanocytes in the dermis, epidermis, and dermal-ectodermal junction, and is thus more akin to human skin. Noonan et al. (2001) subjected albino Hgf/Sf transgenic mice and wildtype littermates to erythemal ultraviolet irradiation at 3.5 days of age, 6 weeks of age, or both. A single neonatal dose, which was 30-fold lower than the total ultraviolet dose administered previously to adult mice, was sufficient to induce melanoma in Hgf/Sf-transgenic mice after a relatively short latent period and with high cumulative incidence. This neonatal dose roughly corresponds to a sunburning dose of natural sunlight at midlatitudes in midsummer. Melanoma development in the transgenic mice after ultraviolet irradiation at both 3.5 days and 6 weeks was indistinguishable from that seen after only a single exposure at 3.5 days, whereas a similar dose at 6 weeks was not tumorigenic. However, the second exposure to ultraviolet light increased the multiplicity of melanocytic lesions as well as the incidence of nonmelanocytic tumors, including squamous cell carcinoma and sarcoma. Melanomas were not seen in either nontransgenic or untreated transgenic mice during the course of the experiment.

Using in situ hybridization and immunoblotting, Powell et al. (2001) detected expression of Hgf and Met in the cerebral wall and ganglionic eminence of the developing mouse forebrain. Using conditioned media and forebrain explants for scatter assays, Powell et al. (2001) concluded that the forebrain exhibits regionally specific motogenic activity attributable to Hgf. Powell et al. (2001) hypothesized that HGF is a key molecular constituent in guiding interneuron migration from the ganglionic eminence to the cerebral cortex.

Jin et al. (2004) found that overexpression of HGF in the retinal pigment epithelium (RPE) in rabbits induced chronic serous retinal detachment with subretinal proliferation of RPE.

Using lentiviral vector technology to deliver uncleavable Hgf to mice, Mazzone et al. (2004) found that uncleavable Hgf inhibited both protease-mediated pro-Hgf conversion and active Hgf-induced Met receptor activation; that local expression of uncleavable Hgf in tumors suppressed tumor growth, impaired tumor angiogenesis, and prevented metastatic dissemination; and that systemic expression of uncleavable Hgf dramatically inhibited the growth of transplanted tumors and abolished the formation of spontaneous metastases without perturbing vital physiologic functions. Mazzone et al. (2004) concluded that proteolytic activation of pro-HGF is a limiting step in tumor progression.

Schultz et al. (2009) generated mice with a conditional knockout of Hgf in the inner ear and observed morphologic defects of the inner ear not seen in littermate controls, including a disorganized tectorial membrane onto which the Reissner membrane was collapsed, thin and flattened stria vascularis with occasional clumps of cellular proliferation, hypoplastic spiral ganglion, and outer hair cell (OHC) degeneration throughout the organ of Corti. MH19-Hgf transgenic mice overexpressing Hgf by 3- to 50-fold had an average 60-dB greater auditory-evoked brainstem response (ABR) threshold compared to littermate controls, consistent with the loss of cochlear amplification due to OHC degeneration. Inspection of the organ of Corti confirmed OHC degeneration in a spatial gradient, from complete OHC loss at the base to near-normal complement of OHCs at the apex; inner hair cells appeared normal.


ALLELIC VARIANTS 3 Selected Examples):

.0001   DEAFNESS, AUTOSOMAL RECESSIVE 39

HGF, SER165SER
SNP: rs137853235, gnomAD: rs137853235, ClinVar: RCV000016089

In 3 affected members of a consanguineous Pakistani family ('family PKDF210') segregating profound prelingual deafness (DFNB39; 608265), Schultz et al. (2009) identified homozygosity for a 495G-A transition in exon 5 of the HGF gene, resulting in a synonymous ser165-to-ser (S165S) substitution. The transition occurs 13 nucleotides into exon 5 relative to the exon 5a splice acceptor site of HGF isoform-1, but at the -3 position (483-3G-A) relative to the exon 5b splice acceptor site of HGF isoform-3, and is predicted to alter the relative strengths of the 2 splice acceptor sites. In vitro assay using a construct with the 495G-A transition produced clones with the exon 5b splice acceptor site exclusively. The 495G-A transition was not found in 1,040 chromosomes from Pakistani, Caucasian, and Human Diversity Panel controls.


.0002   DEAFNESS, AUTOSOMAL RECESSIVE 39

HGF, 3-BP DEL, 1986TGA
SNP: rs1788701297, ClinVar: RCV000016090

In affected members of 36 Pakistani and 2 Indian families segregating recessive profound prelingual deafness (DFNB39; 608265), Schultz et al. (2009) identified homozygosity for a 3-bp deletion (1986delTGA) in intron 4 of the HGF gene, within a highly conserved sequence that is part of the 3-prime untranslated region of a previously undescribed short form of HGF, predicted to encode 24 additional amino acids before encountering a stop codon. Heterozygosity for the 3-bp deletion was found in 2 of 429 Pakistani controls, but the mutation was not found in 415 Caucasian, Indian, or Human Diversity Panel controls.


.0003   DEAFNESS, AUTOSOMAL RECESSIVE 39

HGF, 10-BP DEL, NT482+1991
ClinVar: RCV000016091

In affected members of 2 Pakistani families ('PKDF601' and 'DEM4472') segregating recessive profound prelingual deafness (DFNB39; 608265), Schultz et al. (2009) identified homozygosity for a 10-bp deletion (482+1991delGATGATGAAA) in intron 4 of the HGF gene, within a highly conserved sequence that is part of the 3-prime untranslated region of a previously undescribed short form of HGF, predicted to encode 24 additional amino acids before encountering a stop codon. The 10-bp deletion was not found in 1,688 control chromosomes.


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Contributors:
Ada Hamosh - updated : 9/18/2012
Paul J. Converse - updated : 10/20/2011
Paul J. Converse - updated : 10/28/2010
Cassandra L. Kniffin - updated : 9/15/2009
Marla J. F. O'Neill - updated : 7/30/2009
Marla J. F. O'Neill - updated : 1/19/2005
Jane Kelly - updated : 7/26/2004
Ada Hamosh - updated : 10/29/2003
Ada Hamosh - updated : 2/21/2003
Dawn Watkins-Chow - updated : 6/12/2002
Paul J. Converse - updated : 1/28/2002
Ada Hamosh - updated : 9/21/2001
Moyra Smith - updated : 12/13/1996

Creation Date:
Victor A. McKusick : 12/29/1989

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mark : 12/13/1996
jenny : 12/12/1996
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pfoster : 4/20/1994
carol : 6/30/1992
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supermim : 3/16/1992
carol : 2/22/1992