HGNC Approved Gene Symbol: BTC
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:74,744,759-74,794,523 (from NCBI)
By screening a breast adenocarcinoma cDNA library with mouse Btc as the probe, Sasada et al. (1993) obtained a cDNA encoding human BTC. The deduced 80-amino acid mature protein, which is 77% identical to the mouse sequence, is derived from a 178-amino acid precursor and has 1 potential N-glycosylation site, 6 cysteine residues in the EGF-like units, a transmembrane domain, and lysine and arginine clusters. Northern blot analysis of mouse tissues revealed strong expression of a 3.0-kb transcript in liver and kidney, weaker expression in heart, lung, and intestine, and no expression in brain. Northern blot analysis of human cell lines detected strongest expression in a breast cancer cell line.
The mammalian members of the epidermal growth factor (EGF) family of growth factors include EGF itself (131530), transforming growth factor-alpha (TGFA; 190170), amphiregulin (AREG; 104640), heregulin (HGL; 142445), and betacellulin (BTC). These molecules all are synthesized primarily as transmembrane precursors, and the precursors are processed to mature molecules by proteolytic events.
Watanabe et al. (1994) purified soluble forms of human BTC to homogeneity from the conditioned medium of mouse A9 cells transfected with the human BTC precursor cDNA. Three types of soluble BTC, apparently derived from a single gene, were identified and their biologic activities assessed. Further studies suggested that the primary receptor for BTC is the EGF receptor (EGFR; 131550).
Before ovulation in mammals, a cascade of events resembling an inflammatory and/or tissue remodeling process is triggered by luteinizing hormone (LH; see 152780) in the ovarian follicle. Many LH effects, however, are thought to be indirect because of the restricted expression of its receptor (LHR; 152790) to mural granulosa cells (Peng et al., 1991). Park et al. (2004) demonstrated that LH stimulation in wildtype mouse ovaries induces the transient and sequential expression of the epidermal growth factor family members amphiregulin, epiregulin (602061), and betacellulin. Incubation of follicles with these growth factors recapitulates the morphologic and biochemical events triggered by LH, including cumulus expansion and oocyte maturation. Thus, Park et al. (2004) concluded that these EGF-related growth factors are paracrine mediators that propagate the LH signal throughout the follicle.
Like amphiregulin, betacellulin is a ligand for EGFR. Pathak et al. (1995) demonstrated that Areg and Btc are tightly linked on mouse chromosome 5. Thus, the human BTC gene is probably located in the region 4q13-q21, where the AREG gene is situated.
Park, J.-Y., Su, Y.-Q., Ariga, M., Law, E., Jin, S.-L. C., Conti, M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 303: 682-684, 2004. [PubMed: 14726596] [Full Text: https://doi.org/10.1126/science.1092463]
Pathak, B. G., Gilbert, D. J., Harrison, C. A., Luetteke, N. C., Chen, X., Klagsbrun, M., Plowman, G. D., Copeland, N. G., Jenkins, N. A., Lee, D. C. Mouse chromosomal location of three EGF receptor ligands: amphiregulin (Areg), betacellulin (Btc), and heparin-binding EGF (Hegfl). Genomics 28: 116-118, 1995. [PubMed: 7590736] [Full Text: https://doi.org/10.1006/geno.1995.1116]
Peng, X.-R., Hsueh, A. J. W., LaPolt, P. S., Bjersing, L., Ny, T. Localization of luteinizing hormone receptor messenger ribonucleic acid expression in ovarian cell types during follicle development and ovulation. Endocrinology 129: 3200-3207, 1991. [PubMed: 1954899] [Full Text: https://doi.org/10.1210/endo-129-6-3200]
Sasada, R., Ono, Y., Taniyama, Y., Shing, Y., Folkman, J., Igarashi, K. Cloning and expression of cDNA encoding human betacellulin, a new member of the EGF family. Biochem. Biophys. Res. Commun. 190: 1173-1179, 1993. [PubMed: 8439318] [Full Text: https://doi.org/10.1006/bbrc.1993.1173]
Watanabe, T., Shintani, A., Nakata, M., Shing, Y., Folkman, J., Igarashi, K., Sasada, R. Recombinant human betacellulin: molecular structure, biological activities, and receptor interaction. J. Biol. Chem. 269: 9966-9973, 1994. [PubMed: 8144591]