Ludwig Institute for Cancer Research Uppsala Branch

Research Groups

Signaling Dynamics Group

Section leader

Ingvar Ferby
Ingvar.Ferby(AT)LICR.uu.se
Phone +46 18 160403

Our group is interested in how negative regulatory circuits of the EGF receptor signalling network control fundamental biological processes with implications on:

• Maintenance and differentiation of epithelial stem cells
• Epithelial morphogenesis
• Epithelial carcinogenesis

Spatiotemporal dynamics of the EGF receptor signaling network

The EGF receptor family of growth factor receptors (the ErbB family) regulates complex morphogenetic processes during development and tissue homeostasis. Their deregulated overactivation, on the other hand, contributes to a vast proportion of epithelial cancers. To date we have acquired considerable insight into the signaling pathways triggered upon receptor activation. However, little is known about the negative regulatory circuits that ensure accurate spatial and temporal signal attenuation.

Figure 1:Numerous proteins involved in negative regulation of the EGFR provide spatiotemporal signaling constrains crucial for tissue development and homeostasis. In vivo and in vitro models of mammary epithelial morphogenesis are used as key tools in the lab.

We hypothesize that negative spatiotemporal constrains on growth factor signals, both in a cell intrinsic and lateral manner, play a crucial role in the maintenance of the epithelial stem cells and the fate of their progeny of progenitor and differentiated cells. We are combining molecular cell signaling and proteomic studies with mouse models of epithelial homeostasis and cancer formation using the mammary gland and associated methods as our primary model system. As a key approach putative negative regulators of growth factor receptors and other genes of interest are targeted by lentiviral mediated RNAi on primary mammary epithelial stem cells and transplanted back into cleared fat pads or cultured in 3D to assess their role in mammary stem cell maintenance and epithelial morphogenesis.

Figure 2: Mig6 knock-out mice develop spontaneous tumours in various tissues.

A particular focus of our group is the recently identified negative regulator of EGFR called Mig6 and another related protein Ack1. A few years back we provided evidence that Mig6 is an important tumour suppressor by generating knockout mice that develop a striking variety of hyperplasic lesions and cancers in different tissues (Ferby et al., Nat Med. 2006). Our ongoing projects have uncovered exciting novel mechanisms by which Mig6 regulates epithelial homeostasis and likely acts as a tumour suppressor. In addition to its previously ability to attenuate EGFR activation, we found that Mig6 is a bimodal sensor of EGFR activation that dissociates from EGFR upon inactivation to directly bind to and activate a pro-apoptotic kinase, thereby actively inducing apoptosis during mammary morphogenesis and lumen formation (under revision).

Selected Publications

Original papers:

1. Reschke M., Ferby I., Stephiak E., Seitzer N., Horst D., Wagner E.F., Ullrich A. “Mitogen-inducible gene-6 is a negative regulator of epidermal growth factor receptor signaling in hepatocytes and human hepatocellular carcinoma.“ Hepatology 2010;51:1383-90.

2. Ferby I., Reschke M., Kudlacek O., Knyazev P., Pante G., Amann K., Sommergruber W., Kraut N., Ullrich A., Fässler R., Klein R.“Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumour formation.” Nature Med. 2006;12:568-573.

3. Gutierrez G.J., Vogtlin A., Castro A., Ferby I., Salvagiotto G., Ronai Z., Lorca T., Nebreda A.R. “Meiotic regulation of the CDK activator RINGO/Speedy by ubiquitin-proteasome-mediated processing and degradation.” Nature Cell Biol. 2006;8:1084-1094.

4. Antonio C., Ferby I., Wilhelm H., Jones M., Karsenti E., Nebreda A.R., Vernos I. “ Xkid, a chromokinesin required for chromosome alignment on the metaphase plate.” Cell 2000;102:425-435.

5. Ferby I., Blazquez M., Palmer A., Eritja R., Nebreda A.R. “A novel p34(cdc2)-binding and activating protein that is necessary and sufficient to trigger G(2)/M progression in Xenopus oocytes.” Genes Dev. 2000;13:2177-2189.