The proper development of multicellular organisms requires the coordination of proliferation and differentiation, which is a particular challenge during the formation of the tissues and organs of the body. Numerous studies have shown that receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) or insulin/insulin-like growth factor receptors (InR/IGF-Rs) play prominent roles in signaling cell proliferation and differentiation. Misregulation of both pathways is often causative for tumor development and -progression through their effects on uncontrolled cell growth, inhibition of apoptosis, angiogenesis, and tumor-associated inflammation. Determining how growth and differentiation are coordinated by such pathways is thus essential to understanding normal development, as well as disease states such as cancer. We have recently identified a new a core component required for both insulin and EGFR signaling pathways, the steppke gene. Steppke encodes a guanine nucleotide exchange factor (GEF) of the cytohesin protein family which are regulators of GDP/GTP exchange for members of the ADP ribosylation factor (Arf) of small GTPases. We could demonstrate an essential role of Steppke in insulin-dependent growth regulation in Drosophila larvae (Fuss et al., Nature 2006) and recently also in EGFR-dependent wing and eye development (Hahn et al., JCS 2013). Together, the genetic, biochemical and immunohistochemical data are consistent with the hypothesis that Steppke is part of a protein scaffold at the plasma membrane which provides a signaling platform downstream of receptor kinase signaling. In ongoing projects, we investigate the molecular mechanism of Steppke function in growth regulation and also aging. Along the same lines, we investigate in other projects signaling pathway components that appear to be involved in Calcium signaling in the nervous system, in the physiology of the tracheal system and we are also studying gap junctional communication by members of the innexin protein family.
Selected recent publications:
- Hahn, I., Fuß, B., Peters, A., Werner, T., Sieberg, A., Gosejacob, D., Hoch M. (2013). The Drosophila Arf GEF Steppke controls MAPK activation in EGFR signaling. J Cell Sci 126, 2470-2479.
- Lechner, H., Josten, F., Fuss, B., Lehmann, C., Bauer, R. and Hoch, M. Mutual cross regulation of paracrine signaling and gap junction communication in Drosophila. Dev Biol. 2007, 310:23-34.
- Fuss B, Becker T, Zinke I, Hoch M. 2006. The cytohesin Steppke is essential for insulin signalling in Drosophila. Nature 444: 945-8