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Gene Review

BTC  -  betacellulin

Homo sapiens

Synonyms: Probetacellulin
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Disease relevance of BTC


High impact information on BTC


Chemical compound and disease context of BTC

  • METHODS: From 14 March 1997 to 25 August 2000, 248 patients underwent neoadjuvant androgen ablation followed by BT monotherapy (BTM) or BT combined with external beam (BTC) for treatment of localized prostate cancer [7].

Biological context of BTC


Anatomical context of BTC


Associations of BTC with chemical compounds

  • In addition, we found the presence of endogenous BTC in conditioned medium of VSMCs and an increase of BTC on angiotensin II stimulation [9].
  • In summary, BTC promotes growth and migration of VSMCs through activation of EGFR, ErbB2, and downstream serine/threonine kinases [9].
  • All pro-BTC shedding was blocked by treatment with a broad-spectrum metalloprotease inhibitor (GM6001) [14].
  • Pro-BTC shedding was activated by calcium ionophore (A23187) and by the metalloprotease activator p-aminophenylmercuric acetate (APMA), but not by phorbol esters [14].
  • Culturing cells in calcium-free medium or with the protein kinase Cdelta inhibitor rottlerin, but not with broad-based protein kinase C inhibitors, blocked A23187-activated pro-BTC shedding [14].

Physical interactions of BTC

  • We also show that the binding of neuregulin-1beta to ErbB4 and ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease at low pH, unlike the binding of epidermal growth factor and transforming growth factor-alpha to ErbB1 [15].

Regulatory relationships of BTC

  • Consequently, only NDF, HB-EGF, and BTC significantly stimulated association of phosphatidylinositol kinase activity with ErbB-3 [16].
  • These results demonstrate, for the first time, activated pro-BTC shedding in response to extracellular calcium influx and APMA and provide evidence that ADAM10 mediates constitutive and activated pro-BTC shedding [14].
  • Also, the metalloproteinase inhibitor GM6001 and an anti-BTC neutralizing antibody suppressed the GLP-1 proliferative effect [11].
  • Pretreatment with the phosphatidylinositol 3'-kinase (PI 3'-kinase) inhibitor wortmannin suppressed BTC-induced cyclin D1 mRNA and protein and DNA synthesis activity [17].

Other interactions of BTC

  • BTC also phosphorylated ErbB2 at Tyr877, Tyr1112, and Tyr1248 and induced association of ErbB2 with EGFR, suggesting their heterodimerization in VSMCs [9].
  • Betacellulin (BTC), a novel EGF family ligand, has been shown to be expressed in atherosclerotic lesions and to be a potent growth factor of VSMCs [9].
  • CONCLUSION: These results revealed that HB-EGF, BTC and EPR are expressed not only by epithelial tumor cells, but also by MFH cells [1].
  • AR and BTC moieties were not evident by Northern blot analysis [18].
  • ADAM10 mediates ectodomain shedding of the betacellulin precursor activated by p-aminophenylmercuric acetate and extracellular calcium influx [14].

Analytical, diagnostic and therapeutic context of BTC


  1. Expression of betacellulin, heparin-binding epidermal growth factor and epiregulin in human malignant fibrous histiocytoma. Yamamoto, T., Akisue, T., Marui, T., Nakatani, T., Kawamoto, T., Hitora, T., Nagira, K., Fujita, I., Matsumoto, K., Kurosaka, M. Anticancer Res. (2004) [Pubmed]
  2. Recombinant human betacellulin. Molecular structure, biological activities, and receptor interaction. Watanabe, T., Shintani, A., Nakata, M., Shing, Y., Folkman, J., Igarashi, K., Sasada, R. J. Biol. Chem. (1994) [Pubmed]
  3. Auto-induction and growth stimulatory effect of betacellulin in human pancreatic cancer cells. Kawaguchi, M., Hosotani, R., Kogire, M., Ida, J., Doi, R., Koshiba, T., Miyamoto, Y., Tsuji, S., Nakajima, S., Kobayashi, H., Masui, T., Imamura, M. Int. J. Oncol. (2000) [Pubmed]
  4. Betacellulin-Pseudomonas toxin fusion proteins bind but are not cytotoxic to cells expressing HER4; correlation of EGFR for cytotoxic activity. Mixan, B., Cohen, B.D., Bacus, S.S., Fell, H.P., Siegall, C.B. Oncogene (1998) [Pubmed]
  5. Betacellulin: a mitogen from pancreatic beta cell tumors. Shing, Y., Christofori, G., Hanahan, D., Ono, Y., Sasada, R., Igarashi, K., Folkman, J. Science (1993) [Pubmed]
  6. Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErbB3 receptors. Alimandi, M., Wang, L.M., Bottaro, D., Lee, C.C., Kuo, A., Frankel, M., Fedi, P., Tang, C., Lippman, M., Pierce, J.H. EMBO J. (1997) [Pubmed]
  7. The impact of prostate volume following neoadjuvant androgen deprivation on quality of life and voiding symptoms in patients undergoing permanent prostate brachytherapy. Krupski, T., Bissonette, E.A., Petroni, G.R., Theodorescu, D. Eur. Urol. (2003) [Pubmed]
  8. ErbB2 and ErbB3 do not quantitatively modulate ligand-induced ErbB4 tyrosine phosphorylation. Feroz, K., Williams, E., Riese, D.J. Cell. Signal. (2002) [Pubmed]
  9. Signal transduction of betacellulin in growth and migration of vascular smooth muscle cells. Mifune, M., Ohtsu, H., Suzuki, H., Frank, G.D., Inagami, T., Utsunomiya, H., Dempsey, P.J., Eguchi, S. Am. J. Physiol., Cell Physiol. (2004) [Pubmed]
  10. Differential activation of epidermal growth factor (EGF) receptor downstream signaling pathways by betacellulin and EGF. Saito, T., Okada, S., Ohshima, K., Yamada, E., Sato, M., Uehara, Y., Shimizu, H., Pessin, J.E., Mori, M. Endocrinology (2004) [Pubmed]
  11. Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Buteau, J., Foisy, S., Joly, E., Prentki, M. Diabetes (2003) [Pubmed]
  12. Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta. Riese, D.J., Bermingham, Y., van Raaij, T.M., Buckley, S., Plowman, G.D., Stern, D.F. Oncogene (1996) [Pubmed]
  13. Human betacellulin, a member of the EGF family dominantly expressed in pancreas and small intestine, is fully active in a monomeric form. Seno, M., Tada, H., Kosaka, M., Sasada, R., Igarashi, K., Shing, Y., Folkman, J., Ueda, M., Yamada, H. Growth Factors (1996) [Pubmed]
  14. ADAM10 mediates ectodomain shedding of the betacellulin precursor activated by p-aminophenylmercuric acetate and extracellular calcium influx. Sanderson, M.P., Erickson, S.N., Gough, P.J., Garton, K.J., Wille, P.T., Raines, E.W., Dunbar, A.J., Dempsey, P.J. J. Biol. Chem. (2005) [Pubmed]
  15. The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Bouyain, S., Longo, P.A., Li, S., Ferguson, K.M., Leahy, D.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  16. Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. Beerli, R.R., Hynes, N.E. J. Biol. Chem. (1996) [Pubmed]
  17. Betacellulin and amphiregulin induce upregulation of cyclin D1 and DNA synthesis activity through differential signaling pathways in vascular smooth muscle cells. Shin, H.S., Lee, H.J., Nishida, M., Lee, M.S., Tamura, R., Yamashita, S., Matsuzawa, Y., Lee, I.K., Koh, G.Y. Circ. Res. (2003) [Pubmed]
  18. Co-expression of heparin-binding EGF-like growth factor and related peptides in human gastric carcinoma. Naef, M., Yokoyama, M., Friess, H., Büchler, M.W., Korc, M. Int. J. Cancer (1996) [Pubmed]
  19. Changes in the expression and cytological localization of betacellulin and its receptors (ErbB-1 and ErbB-4) in the trophoblasts in human placenta over the course of pregnancy. Tanimura, K., Nakago, S., Murakoshi, H., Takekida, S., Moriyama, T., Matsuo, H., Hashimoto, K., Maruo, T. Eur. J. Endocrinol. (2004) [Pubmed]
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