HGNC Approved Gene Symbol: TGFA
Cytogenetic location: 2p13.3 Genomic coordinates (GRCh38): 2:70,447,284-70,553,826 (from NCBI)
Transforming growth factors (TGFs) are biologically active polypeptides that reversibly confer the transformed phenotype on cultured cells. TGF-alpha shows about 40% sequence homology with epidermal growth factor (EGF; 131530) and competes with EGF for binding to the EGF receptor (131550), stimulating its phosphorylation and producing a mitogenic response.
Collin et al. (1999) determined the exon-intron structure of the TGFA gene and excluded it as a candidate for Alstrom syndrome (203800).
Brissenden et al. (1985) used a human genomic DNA clone to map the TGFA locus to chromosome 2p13-2p11 in somatic cell hybrids with confirmation by in situ hybridization. They commented on the possible significance of the fact that in Burkitt lymphoma with 2;8 translocation, the breakpoint is at chromosome 2p13-p11. Thus, t(2;8) might place TGFA near the MYC oncogene. Tricoli et al. (1985, 1986) likewise assigned TGFA to chromosome chromosome 2p13 by in situ hybridization. Fowler et al. (1993) demonstrated that the murine Tgfa gene is linked to Igkc (147200), Fabp1 (134650), and Ly-2 (CD8A; 186910) on chromosome 6.
Ellis et al. (1987) presented evidence that TGFA plays a role in certain paraneoplastic manifestations of melanoma: the sign of Leser-Trelat (the sudden appearance of, or increase in the number and size of, seborrheic keratoses), acanthosis nigricans, and eruptive acrochordons (sudden onset of multiple skin tags).
Fernandez-Larrea et al. (1999) used the 2-hybrid screen to identify pro-TGF-alpha cytoplasmic domain-binding proteins, which they referred to as TACIPs (pro-TGF-alpha cytoplasmic domain-interacting proteins), involved in the trafficking of pro-TGF-alpha. They cloned 2 such proteins, which they designated TACIP1 (601017) and TACIP18 (602217).
The circadian clock in the suprachiasmatic nucleus is thought to drive daily rhythms of behavior by secreting factors that act locally within the hypothalamus. In a systematic screen, Kramer et al. (2001) identified TGFA as a likely suprachiasmatic nucleus inhibitor of locomotion. TGFA is expressed rhythmically in the suprachiasmatic nucleus, and when infused into the third ventricle it reversibly inhibited locomotor activity and disrupted circadian sleep-wake cycles. These actions were mediated by EGF receptors on neurons in the hypothalamic subparaventricular zone. Mice with a hypomorphic EGF receptor mutation exhibited excessive daytime locomotor activity and failed to suppress activity when exposed to light. Kramer et al. (2001) concluded that their results implicate EGF receptor signaling in the daily control of locomotor activity. They identified a neural circuit in the hypothalamus that likely mediates the regulation of behavior both by the suprachiasmatic nucleus and the retina using TGFA and EGF receptors in the retinohypothalamic tract.
Franklin et al. (2005) found that PDZ domain 1 of mouse Magi3 (615943) bound to the C-terminal PDZ-recognition motif (TVV) of human pro-TGF-alpha. PDZ domains 2 and 5 interacted weakly with pro-TGF-alpha. Magi3 interacted transiently with the 17-kD cell surface form of pro-TGF-alpha in transfected MDCK cells. Overexpression of Magi3 caused increased secretion of TGF-alpha into the basolateral medium of polarized MDCK cells, suggesting that MAGI3 plays a role in efficient trafficking of TGF-alpha to the cell surface in polarized epithelial cells. Deletion of the C-terminal TVV motif severely reduced TGF-alpha delivery to the cell surface.
Using human cell-based assays, Wunderle et al. (2016) showed that RHBDL4 (617515) triggered secretion of a 37-kD full-length pro-form of TGFA. Under steady-state conditions, the majority of pro-TGFA did not leave the endoplasmic reticulum (ER) and was degraded by ER-associated degradation (ERAD). However, in the presence of ectopically expressed RHBDL4 or inhibition of the proteasome, pro-TGFA was rescued from ERAD and was redirected toward increased ER export and secretion. Truncation analysis revealed that ER export and secretion of pro-TGFA were mediated by its cytoplasmic PDZ-binding domain. Gradient analysis revealed that pro-TGFA was secreted from cells in microvesicles, which was promoted by RHBDL4 and regulated by transactivation.
For discussion of a possible association between variation in TGFA and orofacial clefting, see OFC2 (602966).
Brissenden, J. E., Derynck, R., Francke, U. Transforming growth factor alpha gene (TGFA) maps to human chromosome 2 close to the breakpoint of the t(2;8) variant translocation in Burkitt lymphoma. (Abstract) Cytogenet. Cell Genet. 40: 589 only, 1985.
Collin, G. B., Marshall, J. D., Naggert, J. K., Nishina, P. M. TGFA: exon-intron structure and evaluation as a candidate gene for Alstrom syndrome. (Letter) Clin. Genet. 55: 61-62, 1999. [PubMed: 10066034] [Full Text: https://doi.org/10.1034/j.1399-0004.1999.550111.x]
Ellis, D. L., Kafka, S. P., Chow, J. C., Nanney, L. B., Inman, W. H., McCadden, M. E., King, L. E., Jr. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelat, and multiple acrochordons: a possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. New Eng. J. Med. 317: 1582-1587, 1987. [PubMed: 2825016] [Full Text: https://doi.org/10.1056/NEJM198712173172506]
Fernandez-Larrea, J., Merlos-Suarez, A., Urena, J. M., Baselga, J., Arribas, J. A role for a PDZ protein in the early secretory pathway for the targeting of proTGF-alpha to the cell surface. Molec. Cell 3: 423-433, 1999. [PubMed: 10230395] [Full Text: https://doi.org/10.1016/s1097-2765(00)80470-0]
Fowler, K. J., Mann, G. B., Dunn, A. R. Linkage of the murine transforming growth factor-alpha gene with Igk, Ly-2, and Fabp1 on chromosome 6. Genomics 16: 782-784, 1993. [PubMed: 8100806] [Full Text: https://doi.org/10.1006/geno.1993.1268]
Franklin, J. L., Yoshiura, K., Dempsey, P. J., Bogatcheval, G., Jeyakumar, L., Meise, K. S., Pearsall, R. S., Threadgill, D., Coffey, R. J. Identification of MAGI-3 as a transforming growth factor-alpha tail binding protein. Exp. Cell Res. 303: 457-470, 2005. [PubMed: 15652357] [Full Text: https://doi.org/10.1016/j.yexcr.2004.10.007]
Kramer, A., Yang, F.-C., Snodgrass, P., Li, X., Scammell, T. E., Davis, F. C., Weitz, C. J. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294: 2511-2515, 2001. [PubMed: 11752569] [Full Text: https://doi.org/10.1126/science.1067716]
Tam, J. P., Sheikh, M. A., Solomon, D. S., Ossowski, L. Efficient synthesis of human type alpha transforming growth factor: its physical and biological characterization. Proc. Nat. Acad. Sci. 83: 8082-8086, 1986. [PubMed: 3490662] [Full Text: https://doi.org/10.1073/pnas.83.21.8082]
Tricoli, J. V., Nakai, H., Byers, M. G., Rall, L. B., Bell, G. I., Shows, T. B. Assignment of the gene coding for human TGF-alpha to chromosome 2p13. (Abstract) Cytogenet. Cell Genet. 40: 762 only, 1985.
Tricoli, J. V., Nakai, H., Byers, M. G., Rall, L. B., Bell, G. I., Shows, T. B. The gene for human transforming growth factor alpha is on the short arm of chromosome 2. Cytogenet. Cell Genet. 42: 94-98, 1986. [PubMed: 3459638] [Full Text: https://doi.org/10.1159/000132258]
Wunderle, L., Knopf, J. D., Kuhnle, N., Morle, A., Hehn, B., Adrain, C., Strisovsky, K., Freeman, M., Lemberg, M. K. Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGF-alpha. Sci. Rep. 6: 27342, 2016. Note: Electronic Article. [PubMed: 27264103] [Full Text: https://doi.org/10.1038/srep27342]