Folate receptor 1 (Folate receptor alpha, FOLR1) is a
protein that in humans is encoded by the FOLR1gene.[5][6]
The protein encoded by this gene is a member of the
folate receptor (FOLR) family. Members of this family have a high affinity for
folic acid and for several reduced folic acid derivatives, and mediate delivery of
5-methyltetrahydrofolate to the interior of cells.
Functions
This receptor is responsible for binding to folic acid and its derivatives, which becomes crucial during fetal development. By adding folate supplementation during pregnancy, neural tube defects in the fetus are prevented. Folate derivatives are necessary for important metabolic processes such as DNA, protein and lipid methylation. More importantly, folate plays a major role in DNA replication and cell division, which are common characteristics of rapid growth. Even though it is unclear how folate affects neural tube formation, scientists are certain that without appropriate folate levels, neural tube defects can develop through human and mice studies. Neural tube defects refer to the improper development of the neural tube by not being sealed correctly. This results in exencephaly or spina bifida, both nervous system abnormalities.[7]
This gene is composed of 7
exons; exons 1 through 4 encode the 5'
UTR and exons 4 through 7 encode the
open reading frame. Due to the presence of 2
promoters, multiple
transcription start sites, and
alternative splicing of exons, several transcript variants are derived from this gene. These variants differ in the lengths of 5' and 3' UTR, but they encode an identical
amino acid sequence.[6]
Clinical significance
Schematic model of FRα used as a target in cancer therapy.[8]
FRα, due to its high expression in some tumors, is an attractive therapeutic target for the development of novel anti-cancer agents in order to limit toxic side-effects on off-target tissues.[8]
FRa can be overexpressed by a number of epithelial-derived tumors including ovarian, breast, renal, lung, colorectal, and brain. According to a review published in 2020, elevated expression of FRa was noted in
mesotheliomas (72-100% of cases),
triple-negative breast cancer (35-68% of cases) and epithelial
ovarian cancer (76-89% of cases).[9]
Therefore, antibodies to FRa are being developed for use in
targeted therapies, with one example being
farletuzumab, in a phase III trial for
ovarian cancer. Further, FRa-binding markers have been created in an attempt to visualise FRa-expressing tumors. In 2021, the fluorescent marker
pafolacianine was approved for identification of malignant lesions during surgeries.
Crystallographic structure of FRα protein. The folate is in green, the folate binding site is colored in orange. A Cys66Tyr substitution position induced by a pathogenic variant is represented in red while the disulfide bond between Cys66 and Cys109 is in dark blue. Figure from Mafi et al., 2020[14] Identification of ovarian cancer metastases located on the intestine and mesentery using fluorescence imaging of the folate receptor alpha-binding marker EC17. From Tummers et al., 2016.[15]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Campbell IG, Jones TA, Foulkes WD, Trowsdale J (October 1991). "Folate-binding protein is a marker for ovarian cancer". Cancer Research. 51 (19): 5329–38.
PMID1717147.
Ragoussis J, Senger G, Trowsdale J, Campbell IG (October 1992). "Genomic organization of the human folate receptor genes on chromosome 11q13". Genomics. 14 (2): 423–30.
doi:
10.1016/S0888-7543(05)80236-8.
PMID1330883.
Sadasivan E, Cedeno M, Rothenberg SP (May 1992). "Genomic organization of the gene and a related pseudogene for a human folate binding protein". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1131 (1): 91–4.
doi:
10.1016/0167-4781(92)90103-7.
PMID1581364.
Coney LR, Tomassetti A, Carayannopoulos L, Frasca V, Kamen BA, Colnaghi MI, Zurawski VR (November 1991). "Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein". Cancer Research. 51 (22): 6125–32.
PMID1840502.
Sadasivan E, Rothenberg SP (November 1988). "Molecular cloning of the complementary DNA for a human folate binding protein". Proceedings of the Society for Experimental Biology and Medicine. 189 (2): 240–4.
doi:
10.3181/00379727-189-42804.
PMID3194438.
S2CID36960775.
Yan W, Ratnam M (November 1995). "Preferred sites of glycosylphosphatidylinositol modification in folate receptors and constraints in the primary structure of the hydrophobic portion of the signal". Biochemistry. 34 (44): 14594–600.
doi:
10.1021/bi00044a039.
PMID7578066.
Saikawa Y, Price K, Hance KW, Chen TY, Elwood PC (August 1995). "Structural and functional analysis of the human KB cell folate receptor gene P4 promoter: cooperation of three clustered Sp1-binding sites with initiator region for basal promoter activity". Biochemistry. 34 (31): 9951–61.
doi:
10.1021/bi00031a018.
PMID7632694.
Prasad PD, Ramamoorthy S, Moe AJ, Smith CH, Leibach FH, Ganapathy V (August 1994). "Selective expression of the high-affinity isoform of the folate receptor (FR-alpha) in the human placental syncytiotrophoblast and choriocarcinoma cells". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1223 (1): 71–5.
doi:
10.1016/0167-4889(94)90074-4.
PMID8061055.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4.
doi:
10.1016/0378-1119(94)90802-8.
PMID8125298.
Elwood PC, Nachmanoff K, Saikawa Y, Page ST, Pacheco P, Roberts S, Chung KN (February 1997). "The divergent 5' termini of the alpha human folate receptor (hFR) mRNAs originate from two tissue-specific promoters and alternative splicing: characterization of the alpha hFR gene structure". Biochemistry. 36 (6): 1467–78.
doi:
10.1021/bi962070h.
PMID9063895.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56.
doi:
10.1016/S0378-1119(97)00411-3.
PMID9373149.
Barber RC, Shaw GM, Lammer EJ, Greer KA, Biela TA, Lacey SW, et al. (April 1998). "Lack of association between mutations in the folate receptor-alpha gene and spina bifida". American Journal of Medical Genetics. 76 (4): 310–7.
doi:
10.1002/(SICI)1096-8628(19980401)76:4<310::AID-AJMG6>3.0.CO;2-T.
PMID9545095.
Folate receptor 1 (Folate receptor alpha, FOLR1) is a
protein that in humans is encoded by the FOLR1gene.[5][6]
The protein encoded by this gene is a member of the
folate receptor (FOLR) family. Members of this family have a high affinity for
folic acid and for several reduced folic acid derivatives, and mediate delivery of
5-methyltetrahydrofolate to the interior of cells.
Functions
This receptor is responsible for binding to folic acid and its derivatives, which becomes crucial during fetal development. By adding folate supplementation during pregnancy, neural tube defects in the fetus are prevented. Folate derivatives are necessary for important metabolic processes such as DNA, protein and lipid methylation. More importantly, folate plays a major role in DNA replication and cell division, which are common characteristics of rapid growth. Even though it is unclear how folate affects neural tube formation, scientists are certain that without appropriate folate levels, neural tube defects can develop through human and mice studies. Neural tube defects refer to the improper development of the neural tube by not being sealed correctly. This results in exencephaly or spina bifida, both nervous system abnormalities.[7]
This gene is composed of 7
exons; exons 1 through 4 encode the 5'
UTR and exons 4 through 7 encode the
open reading frame. Due to the presence of 2
promoters, multiple
transcription start sites, and
alternative splicing of exons, several transcript variants are derived from this gene. These variants differ in the lengths of 5' and 3' UTR, but they encode an identical
amino acid sequence.[6]
Clinical significance
Schematic model of FRα used as a target in cancer therapy.[8]
FRα, due to its high expression in some tumors, is an attractive therapeutic target for the development of novel anti-cancer agents in order to limit toxic side-effects on off-target tissues.[8]
FRa can be overexpressed by a number of epithelial-derived tumors including ovarian, breast, renal, lung, colorectal, and brain. According to a review published in 2020, elevated expression of FRa was noted in
mesotheliomas (72-100% of cases),
triple-negative breast cancer (35-68% of cases) and epithelial
ovarian cancer (76-89% of cases).[9]
Therefore, antibodies to FRa are being developed for use in
targeted therapies, with one example being
farletuzumab, in a phase III trial for
ovarian cancer. Further, FRa-binding markers have been created in an attempt to visualise FRa-expressing tumors. In 2021, the fluorescent marker
pafolacianine was approved for identification of malignant lesions during surgeries.
Crystallographic structure of FRα protein. The folate is in green, the folate binding site is colored in orange. A Cys66Tyr substitution position induced by a pathogenic variant is represented in red while the disulfide bond between Cys66 and Cys109 is in dark blue. Figure from Mafi et al., 2020[14] Identification of ovarian cancer metastases located on the intestine and mesentery using fluorescence imaging of the folate receptor alpha-binding marker EC17. From Tummers et al., 2016.[15]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Campbell IG, Jones TA, Foulkes WD, Trowsdale J (October 1991). "Folate-binding protein is a marker for ovarian cancer". Cancer Research. 51 (19): 5329–38.
PMID1717147.
Ragoussis J, Senger G, Trowsdale J, Campbell IG (October 1992). "Genomic organization of the human folate receptor genes on chromosome 11q13". Genomics. 14 (2): 423–30.
doi:
10.1016/S0888-7543(05)80236-8.
PMID1330883.
Sadasivan E, Cedeno M, Rothenberg SP (May 1992). "Genomic organization of the gene and a related pseudogene for a human folate binding protein". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1131 (1): 91–4.
doi:
10.1016/0167-4781(92)90103-7.
PMID1581364.
Coney LR, Tomassetti A, Carayannopoulos L, Frasca V, Kamen BA, Colnaghi MI, Zurawski VR (November 1991). "Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein". Cancer Research. 51 (22): 6125–32.
PMID1840502.
Sadasivan E, Rothenberg SP (November 1988). "Molecular cloning of the complementary DNA for a human folate binding protein". Proceedings of the Society for Experimental Biology and Medicine. 189 (2): 240–4.
doi:
10.3181/00379727-189-42804.
PMID3194438.
S2CID36960775.
Yan W, Ratnam M (November 1995). "Preferred sites of glycosylphosphatidylinositol modification in folate receptors and constraints in the primary structure of the hydrophobic portion of the signal". Biochemistry. 34 (44): 14594–600.
doi:
10.1021/bi00044a039.
PMID7578066.
Saikawa Y, Price K, Hance KW, Chen TY, Elwood PC (August 1995). "Structural and functional analysis of the human KB cell folate receptor gene P4 promoter: cooperation of three clustered Sp1-binding sites with initiator region for basal promoter activity". Biochemistry. 34 (31): 9951–61.
doi:
10.1021/bi00031a018.
PMID7632694.
Prasad PD, Ramamoorthy S, Moe AJ, Smith CH, Leibach FH, Ganapathy V (August 1994). "Selective expression of the high-affinity isoform of the folate receptor (FR-alpha) in the human placental syncytiotrophoblast and choriocarcinoma cells". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1223 (1): 71–5.
doi:
10.1016/0167-4889(94)90074-4.
PMID8061055.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4.
doi:
10.1016/0378-1119(94)90802-8.
PMID8125298.
Elwood PC, Nachmanoff K, Saikawa Y, Page ST, Pacheco P, Roberts S, Chung KN (February 1997). "The divergent 5' termini of the alpha human folate receptor (hFR) mRNAs originate from two tissue-specific promoters and alternative splicing: characterization of the alpha hFR gene structure". Biochemistry. 36 (6): 1467–78.
doi:
10.1021/bi962070h.
PMID9063895.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56.
doi:
10.1016/S0378-1119(97)00411-3.
PMID9373149.
Barber RC, Shaw GM, Lammer EJ, Greer KA, Biela TA, Lacey SW, et al. (April 1998). "Lack of association between mutations in the folate receptor-alpha gene and spina bifida". American Journal of Medical Genetics. 76 (4): 310–7.
doi:
10.1002/(SICI)1096-8628(19980401)76:4<310::AID-AJMG6>3.0.CO;2-T.
PMID9545095.