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Non-proliferative signaling by negative regulation of the Raf kinase cascade

English title Non-proliferative signaling by negative regulation of the Raf kinase cascade
Applicant Mölling Karin
Number 105829
Funding scheme Project funding (Div. I-III)
Research institution Institut für Medizinische Virologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.10.2004 - 30.09.2006
Approved amount 199'207.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Cellular Biology, Cytology

Keywords (5)

Contact inhibition; Differentiation; PDZ-domains; Raf kinase cascade; Quiescence kinase

Lay Summary (English)

Lead
Lay summary
The Ras-Raf-MEK-ERK signalling cascade is of considerable interest since many human cancers result from constitutive activation of this pathway. In normal cells this pathway is tightly controlled and regulates proliferation, differentiation and survival of cells. Previously we demonstrated a crosstalk between the Raf-MEK-ERK protein kinase cascade and the PI3K-Akt pathway. This crosstalk decides whether cells will proliferate or differentiate (Zimmermann S and Moelling K. Science. 1999; 286:1741-4; Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ. Science. 1999; 286:1738-41).We continued this study using the adipocyte differentiation system. Although inhibition of the PI3K pathway enhanced phosphorylation of ERK, the crosstalk seems not to play a role. Instead, the protein kinase RIP2 may replace MEK and allow a bypass of the classical Raf-MEK-ERK pathway. That this can be indeed the case we demonstrated in human monocyte-derived dendritic cells, which are highly potent antigen presenting cells. Lipopolysaccharide, the major component of the gram-negative bacterial cell wall, activates the Raf/RIP2 pathway, which regulates the production of the pro-inflammatory cytokine IL-12. Thus the Raf/RIP2 pathway can mediate innate immunity (Usluoglu N, Pavlovic J, Moelling K and Radziwill G. Eur J Immunol., revised version submitted). Furthermore we are characterizing the protein AF-6, a junctional adhesion protein that is a negative regulator of the Ras-Raf-MEK-ERK pathway. AF-6 is a multidomain protein with properties of a tumour suppressor, which we described in a previous study. Here we cloned and analysed the isoform AF6i3. Our data indicate that the AFi3 protein stabilizes E-cadherin-dependent adhesion during dynamic processes, such as wound closure and formation of cell junctions. The protein may play a role in human diseases such as the cleft lip syndrom (Lorger M and Moelling K . J Cell Sci. 2006; 119:3385-98).Apart from Ras, the proto-oncoprotein c-Src is the second main activator of Raf. c-Src is a tyrosine kinase involved in cell adhesion, motility and proliferation. Elevated c-Src protein expression and elevated kinase activity correlate with tumourigenesis. We identified c-Src as a target for the PDZ domain of AF-6. The PDZ protein recruits c-Src to specific regions of a cell and restricts the kinase activity of c-Src and the number of substrates phopshorylated. This novel type of regulation of c-Src through binding to PDZ domains may help to reduce the risk of malignant transformation (Radziwill G, Weiss A, Heinrich J, Baumgartner M, Boisguerin P, Owada K and Moelling K. EMBO Journal. 2007, in press).
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
61965 Signalling of the Raf-kinase in complex biological systems 01.12.2000 Project funding (Div. I-III)

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