Betacellulin

Betacellulin is a protein that in humans is encoded by the BTC gene 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). As the role a EGFR, betacellulin is manifested by different form of muscles and tissues, it also has a great effect of nitrogen that is used for 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.

BTC
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesBTC, entrez:685, betacellulin
External IDsOMIM: 600345 MGI: 99439 HomoloGene: 1309 GeneCards: BTC
Orthologs
SpeciesHumanMouse
Entrez

685

12223

Ensembl

ENSG00000174808

ENSMUSG00000082361

UniProt

P35070

Q05928

RefSeq (mRNA)

NM_001729
NM_001316963

NM_007568

RefSeq (protein)

NP_001303892
NP_001720

NP_031594

Location (UCSC)Chr 4: 74.74 – 74.79 MbChr 5: 91.51 – 91.55 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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]

Figure 2. The transcription and translation product of betacellulin gene

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.

Clinical significance

Therapy resistance

This caused the therapy resistance in glioblastoma (GBM). The transcription factor signal transducer and activator of transcription 3 (STAT3) was identified as the therapeutic target for glioblastoma.[10] However, inhibition of STAT3 induces the production of betacellulin in which will bind and activate EGFR.[10] As results, nuclear factor-kappaB (NF-κB), a major mediator of resistance in GBM, is also activated.[10] Inhibition of STAT3 and betacellulin results in apoptosis in glioblastoma cells.[10] This indicates that BTC has a role in regulation of tumor cell growth.

Ovarian cancer cell migration

The ability to bind and activate the homodimer or heterodimer of the ERBB receptors may give some special properties to BTC. This was presented in the study of betacellulin in ovarian cancer progression. Activation of EGFR up-regulating the Cx43 that is relating to the development and migration of ovarian cancer. Betacellulin is responsible for binding and activating the EGFR which means betacellulin up-regulates Cx43 expression and cell migration.[11] Betacellulin increased Connexin43 expression and increased cell migration in two human ovarian cancer cell line (OVCAR4 and SKOV3.)[11] This was also observed in Zhao's study.[12] The difference is that betacellulin helps cancer cell migration by down-regulated E-cadherin, and this results in increasing cell migration in OVCAR5 and SKOV3 human ovarian cancer cell line.[12]

Regulation in osteoblasts

Osteoblasts, which are responsible for forming and mineralizing osteoid, express EGFRs and alter rates of proliferation and differentiation in response to EGF receptor activation. Transgenic mice over-expressing the EGF-like ligand betacellulin (BTC) exhibit increased cortical bone deposition; however , because the transgene is ubiquitously expressed in these mice, the identity of cells affected by BTC and responsible for increased cortical bone thickness remains unknown. BTC decreases the expression of osteogenic markers in both MSCs (mesenchymal stem cell) and pre-osteoblasts increases in proliferation require hypoxia-inducible factor-alpha (HIF-alpha), as an HIF antagonist prevents BTC-driven proliferation. Both MSCs and pre-osteoblasts express EGF receptors ErbB1, ErbB2, and ErbB3, with no change in expression under osteogenic differentiation. These are the first data that demonstrate an influence of BTC upon MSCs and the first to implicate HIF-alpha in BTC-mediated proliferation.

References
  1. GRCh38: Ensembl release 89: ENSG00000174808 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000082361 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: betacellulin".
  6. 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. PMID 24440602.
  7. 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. PMID 24440602.
  8. Reid M (2007-07-23). "Faculty Opinions recommendation of Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IkappaBalpha". {{cite journal}}: Cite journal requires |journal= (help)
  9. Wang Y, Zhang F, Zhang Y, Shan Q, Liu W, Zhang F, et al. (March 2021). "Betacellulin regulates peripheral nerve regeneration by affecting Schwann cell migration and axon elongation". Molecular Medicine. 27 (1): 27. doi:10.1186/s10020-021-00292-5. PMC 8015203. PMID 33794764.
  10. Fan Q, An Z, Wong RA, Luo X, Lu ED, Baldwin A, et al. (April 2020). "Betacellulin drives therapy resistance in glioblastoma". Neuro-Oncology. 22 (4): 457–469. doi:10.1093/neuonc/noz206. PMC 7158663. PMID 31678994.
  11. Zhao J, Klausen C, Yi Y, Cheng JC, Chang HM, Leung PC (January 2020). "Betacellulin enhances ovarian cancer cell migration by up-regulating Connexin43 via MEK-ERK signaling". Cellular Signalling. 65: 109439. doi:10.1016/j.cellsig.2019.109439. PMID 31654720. S2CID 204976230.
  12. Zhao J, Klausen C, Qiu X, Cheng JC, Chang HM, Leung PC (May 2016). "Betacellulin induces Slug-mediated down-regulation of E-cadherin and cell migration in ovarian cancer cells". Oncotarget. 7 (20): 28881–28890. doi:10.18632/oncotarget.7591. PMC 5045363. PMID 27129169.

Further reading

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