DICKKOPF

"Biophysical and structural studies on Wnt-regulatory complexes of LRP5/6, Dickkopf and Kremen"

Coordinatore	THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD    more  Organization address address: University Offices, Wellington Square city: OXFORD postcode: OX1 2JD contact info Titolo: Dr. Nome: Stephen Cognome: Conway Email: send email Telefono: +44 1865 289800 Fax: +44 1865 289801
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	209˙092 €
EC contributo	209˙092 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2010-IEF
Funding Scheme	MC-IEF
Anno di inizio	2011
Periodo (anno-mese-giorno)	2011-07-01   -   2013-06-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD  Organization address address: University Offices, Wellington Square city: OXFORD postcode: OX1 2JD contact info Titolo: Dr. Nome: Stephen Cognome: Conway Email: send email Telefono: +44 1865 289800 Fax: +44 1865 289801	UK (OXFORD)	coordinator	209˙092.80

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 Obiettivo del progetto (Objective)

'Orchestration of developmental processes as well as function and homeostasis of tissues depend on fine tuned intercellular communication, necessitating carefully controlled extracellular gradients of a wide range of signalling molecules. Signalling by the Wnt family of secretory glycolipoproteins is renowned for its crucial roles in embryonic development and tissue homeostasis and is subject to a multi-layered system of regulation. Conversely, dysregulation of Wnt signalling is implicated in developmental defects, degenerative diseases, and cancer. Dickkopf (Dkk) proteins are secreted regulators of canonical Wnt/β-catenin signalling, which compete with the Wnt morphogens for their coreceptors LRP5 and -6. A second class of cell surface Dkk receptors, called Kremen (Krm1 and -2), amplify Dkk function by promoting cell surface expression of LRP5/6 in the absence of Dkk and inducing a rapid internalization in its presence. The goal of this proposal is to elucidate the molecular mechanisms behind the Wnt-regulatory activity of Dkk and Krm. I will use protein produced by transient secretory mammalian expression to reconstitute binary and ternary complexes of LRP5/6, Dkk, and Krm in vitro. A wide range of biophysical methods including analytical ultracentrifugation and surface plasmon resonance will be applied to characterize complex formation with respect to stoichiometry, minimal functional modules, affinity and kinetics. X-ray crystallization and electron microscopy will be used to study the structures of isolated complex components and the structural changes associated with complex formation. Based on biophysical and structural data, functional mutants of the proteins will be created and tested in a cellular setting using e.g. a Wnt-responsive bioluminescence reporter assay or confocal microscopy. By studying the interaction of LRP5/6, Dkk and Krm, I shall provide a new level of insight into the regulation of the Wnt signalling system.'

Introduzione (Teaser)

Dysfunction in regulation of extracellular signalling pathways plays a role in cancer. EU-funded scientists have provided a high-resolution view of cell surface molecular interactions that could be potential therapy targets.