Betacellulin is a protein that in humans is encoded by the BTCgene located on chromosome 4 at locus 4q13-q21.[5] Betacellulin was initially identified as a mitogen.[6] Betacellulin, is a part of an Epidermal Growth Factor (EGF) family and functions as a ligand for the epidermal growth factor receptor (EGFR). The role of betacellulin as an EGF is manifested differently in various tissues, and it has a great effect on nitrogen signaling in retinal pigment epithelial cells and vascular smooth muscle cells. While many studies attest a role for betacellulin in the differentiation of pancreatic β-cells, the last decade witnessed the association of betacellulin with many additional biological processes, ranging from reproduction to the control of neural stem cells.[6] Betacellulin is a member of the EGF family of growth factors. It is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events.
Structure
As shown on figure 1, the secondary structure of the human betacellulin-2 has 6% helical (1 helices; 3 residues) 36% beta sheet (5 strands; 18 residues). The mRNA of betacellulin contains six exons in which is 2816 base-pair long.[6] The mRNA was translated into 178 amino acids, and different regions of the amino acid are responsible for different function.[6] The first 31 amino acids are responsible for the signal peptide (Figure 2, exon 1), the 32nd to 118th amino acids are responsible for the extracellular region (Figure 2, exon 2 and 3), the 65-105 amino acids are responsible for the EGF-like domain (Figure 2, exon 3), the transmembrane domain is from amino acids 119-139 (Figure 2, exon 4), the cytoplasmic tail is from amino acid 140-178 (Figure 2, exon 5).[6]
Figure 1. NMR Structure of Human Betacellulin-2
Figure 2. The transcription and translation product of betacellulin gene
Function
As a typical EGFR ligand, betacellulin is expressed by a variety of cell types and tissues, the post-translation of the betacellulin can ectodomain shedding, and the proteolytic release the soluble factors can bind and activate the homodimer or heterodimer of the ERBB receptors. The membrane-anchored form of the betacellulin can activate the epidermal growth factor receptor (EGFR).[7]
Betacellulin stimulates the proliferation of retinal pigment epithelial and vascular smooth muscle cells but did not stimulate the growth of several other cell types, such as endothelial cells and fetal lung fibroblasts.[8]
Tissue distribution
The mRNA coding for betacellulin was found to be slightly higher compared in the rat sciatic nerve segment after nerve damage, suggesting that betacellulin can play a role in peripheral nerve regeneration. Immunohistochemistry has been used to look for betacellulin expression in Schwann cells. Treating cells with betacellulin recombinant protein can be used to investigate the role of betacellulin in managing Schwann cells. A co-culture assay can also used to assess the effect of Schwann cell-secreted betacellulin on neurons.[9]
Mouse BTC is expressed as a 178-amino acid precursor. The membrane-bound precursor is cleaved to yield mature secreted mouse BTC. BTC is synthesized in a wide range of adult tissues and in many cultured cells, including smooth muscle cells and epithelial cells. The amino acid sequence of mature mouse BTC is 82.5%, identical with that of human BTC, and both exhibit significant overall similarity with other members of the EGF family.
^ abcdeDahlhoff M, Wolf E, Schneider MR (April 2014). "The ABC of BTC: structural properties and biological roles of betacellulin". Seminars in Cell & Developmental Biology. 28: 42–48. doi:10.1016/j.semcdb.2014.01.002. PMID24440602.
^Dahlhoff M, Wolf E, Schneider MR (April 2014). "The ABC of BTC: structural properties and biological roles of betacellulin". Seminars in Cell & Developmental Biology. 28: 42–48. doi:10.1016/j.semcdb.2014.01.002. PMID24440602.
^Sethi G, Ahn KS, Chaturvedi MM, Aggarwal BB (15 November 2007). "Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα". Oncogene. 26 (52): 7324–7332. doi:10.1038/sj.onc.1210544. PMID17533369. S2CID25253064. (Erratum: doi:10.1038/onc.2015.313, PMID26473948, Retraction Watch. If the erratum has been checked and does not affect the cited material, please replace {{erratum|...}} with {{erratum|...|checked=yes}}.)
Yamamoto T, Akisue T, Marui T, Nakatani T, Kawamoto T, Hitora T, et al. (2004). "Expression of betacellulin, heparin-binding epidermal growth factor and epiregulin in human malignant fibrous histiocytoma". Anticancer Research. 24 (3b): 2007–2010. PMID15274392.
Nakagawa T, Furuta H, Sanke T, Sakagashira S, Shimomura H, Shimajiri Y, et al. (June 2005). "Molecular scanning of the betacellulin gene for mutations in type 2 diabetic patients". Diabetes Research and Clinical Practice. 68 (3): 188–192. doi:10.1016/j.diabres.2004.09.019. PMID15936459.
Silver KD, Shi X, Mitchell BD (April 2007). "Betacellulin variants and type 2 diabetes in the Old Order Amish". Experimental and Clinical Endocrinology & Diabetes. 115 (4): 229–231. doi:10.1055/s-2007-970575. PMID17479438.
Dunbar AJ, Goddard C (August 2000). "Structure-function and biological role of betacellulin". The International Journal of Biochemistry & Cell Biology. 32 (8): 805–815. doi:10.1016/S1357-2725(00)00028-5. PMID10940639.
Silver KD, Magnuson VL, Tolea M, Wang J, Hagopian WA, Mitchell BD (July 2006). "Association of a polymorphism in the betacellulin gene with type 1 diabetes mellitus in two populations". Journal of Molecular Medicine. 84 (7): 616–623. doi:10.1007/s00109-006-0052-6. PMID16683131. S2CID31302931.
