Growth Control Group (CRUK) - Sir William Dunn School of Pathology
The structure and function of the IGF2
Our aim is to characterise the protein-protein interactions between the IGF2
ligand and the IGF2 receptor, as well as the interactions of
mannose-6-phosphate containing ligands, such as lysosomal enzymes, with other
domains of the same receptor. Site directed mutagenesis and surface plasmon
resonance (BIAcore) of recombinant proteins form the basis of a systematic
analysis of the interacting amino acids and general stereochemistry involved in
these ligand receptor interactions. Other studies include the directed
evolution of IGF2R using surface display libraries and time-resolved analysis
of cargo driven subcellular localisation of the receptor. The group
collaborates closely with structural biologists at the University of Bristol
(Professor Matt Crump) and at the University of Oxford (Professor Yvonne Jones,
functional genetic interactions of Igf2 and Igf2r in conditional murine models.
The gene expressing IGF2 (Igf2) is reciprocally imprinted with respect to
the gene expressing the IGF2 receptor (Igf2r). Modification of DNA methylation
and genomic imprinting implicate a role for loss of imprinting of IGF2 as a
functional modifier of cancer risk. The purpose is to quantify allelic supply
of the ligand and receptor in established genetic models of cancer progression.
The initial focus has been on the functional genetics of Igf2 and Igf2r. These
experiments are being extended to other tumour susceptiblity models using Cre
mediated conditional gene disruption. The ultimate aim is to investigate the functional
consequences of cell type domain specific expression within tumours, and their
functional significance in tumour growth control.
identification and validation of IGF2 biomarkers
This research project is
concerned with defining the specificity of insulin-like growth factor 2 (IGF2)
signalling and uses microarray gene expression profiling, imaging and
bioinformatic approaches to identify biomarkers associated with excess supply
of IGF2 ligand.
The generation and
development of soluble forms of the IGF2 receptor domain 11 as ligand trap for
The purpose is to
functionally evaluate therapeutic proteins that function as ligand traps for
IGF2. The experiments focus on generating novel
forms of sIGF2R based on
domain 11 of the receptor, evaluating ligand binding properties using surface
plasmon resonance, and generating
cell systems as assays. Collaboration with Cancer Research Technology aims to
exploit these molecules for development
and testing in early
phase clinical trials run by the group in the Oxford Cancer Centre.
research in bone and soft tissue sarcoma.
Bone sarcoma are high grade tumours that occur in young people. The
current treatments result in 60% of patients being cured, but these treatments
are associated with side effects. We are studying biomarkers that may influence
treatment decisions and that will be tested in clincial trials. We collaborate
with pathologists and surgeons at the Nuffield Orthopaedic Centre and other
centres across Europe.
The HealthTIES consortium joins
five of Europe’s top regions for healthcare technology and addresses Europe’s
greatest health challenges: an ageing population and the sustainability of the
healthcare system. The aim is to speed
up the cycle of innovation and make the EU a world-class player in healthcare