Molecular mechanisms of growth regulation

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Molecular Mechanisms of Growth Regulation

Growth factors play essential roles in the maintenance of tissue homeostasis. Growth factors may act at distant sites (endocrine modus) or locally (paracrine, juxtacrine, and autocrine modus). The tyrosine kinase epidermal growth factor receptor (EGFR, ERBB1, HER1) and the related receptors ERBB2 (neu), ERBB3, and ERBB4 form one of the most potent signaling systems in biology, regulating many aspects of cell fate. Canonical EGFR activation is accomplished by the interaction with seven related growth factors: amphiregulin (AREG), betacellulin (BTC), epidermal growth factor (EGF), epigen (EPGN), epiregulin (EREG), heparin-binding EGF-like growth factor (HBEGF) and transforming growth factor alpha (TGFA). Transgenic mice overexpressing specific members of this family are excellent models for studying the functions of the protein in question and its potential involvement in diseases. In a complementary approach, mice carrying „floxed“ alleles of particular genes, can be employed to study the consequences of the general of tissue- and time-specific loss of the corresponding protein.
In the past, we have characterized the effects of overexpressing the EGFR ligands betacellulin (Schneider et al., 2005), EGF (Klonisch et al., 2009), and Epigen (Dahlhoff et al., 2010). At the moment, three further transgenic mouse lines overexpressing EGFR ligands in a tissue-specific manner are being evaluated. In addition, we are employing mice with floxed alleles of different ERBBs in order to evaluate the consequences of their loss in a tissue-specific manner. In current projects we focus on the role of the EGFR system in the skin, in bones (particularly regarding the mediation of the bone anabolic action of the parathyroid hormone), and the exocrine pancreas (particularly the protective role against acute pancreatitis).