Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 605776

FIBRINOGEN-LIKE 1; FGL1

Alternative titles; symbols

HEPASSOCIN

HGNC Approved Gene Symbol: FGL1

Cytogenetic location: 8p22 Genomic coordinates (GRCh38) : 8:17,864,389-17,895,538 (from NCBI)

TEXT

For general information on fibrinogen and fibrinogen-like proteins, see FGA (134820), FGB (134830), FGG (134850), and FGL2 (605351).

Cloning and Expression

Using subtractive and differential cDNA cloning to identify a gene overexpressed in a hepatocellular carcinoma, Yamamoto et al. (1993) isolated a cDNA encoding FGL1, which they called HFREP1. The deduced 312-amino acid FGL1 protein possesses a hydrophobic leader peptide. FGL1 shares significant sequence homology with FGB and FGG and with other fibrinogen-related proteins. The FGL1 sequence includes 4 cysteine residues that are widely conserved in all fibrinogens and fibrinogen-related proteins. However, FGL1 does not contain several regions conserved among fibrinogens that are important in the coagulation cascade. Yamamoto et al. (1993) hypothesized that FGL1 is a secretory protein with a function that does not involve coagulation. Northern blot analysis of 12 rat tissues detected liver-specific expression of Fgl1. Additional Northern blot analysis detected a 1.2-kb FGL1 transcript in human hepatocellular carcinoma cell lines, leading Yamamoto et al. (1993) to conclude that FGL1 may be involved in the development of hepatocellular carcinoma.

By screening a liver cell cDNA library with the rat FGL1 cDNA as probe, Hara et al. (2001) cloned human FGL1. They found 83.8% identity between the human and rat protein sequences after removal of the signal peptide; neither sequence was found to contain likely N-glycosylation sites. Northern dot blot detected abundant expression in only adult and fetal liver samples and weak expression in pancreas.

Mapping

Gross (2019) mapped the FGL1 gene to chromosome 8p22 based on an alignment of the FGL1 sequence (GenBank AF168954) with the genomic sequence (GRCh38).

Gene Function

Hara et al. (2001) purified recombinant FGL1 from transfected CHO cells. Study of assays of [3H]thymidine incorporation into the DNA of primary hepatocytes showed that FGL1 has mitogenic activity and that the active species is a 68-kD dimer.

Wang et al. (2019) found that FGL1 bound LAG3 (153337) with high specificity in both human and mouse. The interaction involved the fibrinogen-like domain of FGL1 and 2 of the 4 Ig-like extracellular domains of LAG3. Functional analysis showed that Fgl1 was an inhibitory ligand of Lag3 that mediated T-cell suppression in mouse. Database analysis and immunofluorescence assays demonstrated that FGL1 was upregulated in human cancers, especially in nonsmall cell lung carcinoma (NSCLC). Elevated FGL1 in plasma was associated with poor outcome in metastatic NSCLC patients having anti-PD1 (PDCD1; 600244) therapy.

Animal Model

Wang et al. (2019) found that Fgl1 knockout did not affect development or growth of mice, but that the mice developed spontaneous autoimmune symptoms as they aged. Disruption of the Fgl1-Lag3 interaction by knockout or antibody blockade in mice promoted T-cell immunity against tumor growth and resulted in significantly slower tumor growth compared with wildtype mice.

REFERENCES

  1. Gross, M. B.Personal Communication. Baltimore, Md. 2/22/2019.
  2. Hara, H., Yoshimura, H., Uchida, S., Toyoda, Y., Aoki, M., Sakai, Y., Morimoto, S., Shiokawa, K.Molecular cloning and functional expression analysis of a cDNA for human hepassocin, a liver-specific protein with hepatocyte mitogenic activity. Biochim. Biophys. Acta 1520: 45-53, 2001. [PubMed: 11470158] [Full Text: https://doi.org/10.1016/s0167-4781(01)00249-4\]
  3. Wang, J., Sanmamed, M. F., Datar, I., Su, T. T., Ji, L., Sun, J., Chen, L., Chen, Y., Zhu, G., Yin, W., Zheng, L., Zhou, T., and 9 others.Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176: 334-347, 2019. [PubMed: 30580966] [Full Text: https://doi.org/10.1016/j.cell.2018.11.010\]
  4. Yamamoto, T., Gotoh, M., Sasaki, H., Terada, M., Kitajima, M., Hirohashi, S.Molecular cloning and initial characterization of a novel fibrinogen-related gene, HFREP-1. Biochem. Biophys. Res. Commun. 193: 681-687, 1993. [PubMed: 8390249] [Full Text: https://doi.org/10.1006/bbrc.1993.1678\]

Contributors:

Matthew B. Gross - updated : 02/22/2019
Bao Lige - updated : 02/22/2019
Patricia A. Hartz - updated : 05/08/2002

Creation Date:

Dawn Watkins-Chow : 3/26/2001

Edit History:

mgross : 02/22/2019
mgross : 02/22/2019
carol : 05/08/2002
mgross : 3/26/2001