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Identification and functional characterisation of novel APC binding partners

Objective

Adenomatous polyposis coli (APC) is an important tumour suppressor in the human colon epithelium: its loss of function is known to be a primary cause of tumourigenesis, accounting for more than 80% of all heritable and spontaneous colon cancers.

The first significant clue for APC function emerged when its association with b-catenin was discovered, providing a molecular link between APC and the Wnt signalling pathway.

The Wnt-signalling cascade is strictly conserved from flies to mammals and controls decisive steps in development and homeostasis of tissues and organs. APC is involved in the regulation of b-catenin at the protein level and the nuclear shuttling of b-catenin.

However, the molecular mechanisms underlying this functions are far from being solved a t present. APC also associates with the plasma membrane at adhesive sites in polarized epithelia. Recent work in mammalian cells and the characterisation of a loss-of-function mutation in Drosophila E-APC suggest novel roles of APC in intercellular adhesion and cell migration.

This proposal combines genetic and biochemical screens to identify most, if not all genes involved in APC function. In particular, we aim to identify APC-binding partners whose binding is abrogated by the (loss-of-function) N175K mutation of E-APC.

This will provide novel insights into the molecular mechanisms underlying this loss-of-function mutation. The thorough characterisation of identified genes will lead to a better understanding of Wnt-signal transduction, but also uncover the variety of APC's cellular functions.

The analysis of APC's role at the plasma membrane and its putative impact on regulating cellular adhesion may have important implications for human malignancies, as they may contribute to tumour progression and metastasis.

Our goal to completely understand the tumour suppressor activity of APC may therefore provide new avenues for therapeutic interventions.

Call for proposal

FP6-2002-MOBILITY-5
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Coordinator

MEDICAL RESEARCH COUNCIL
Address
20 Park Crescent
London
United Kingdom