Receptors, Signaling & Proteomics - Research Activities

Transforming Growth Factor (TGF)-b Signalling

Epidermal Growth Factor (EGF) Signalling

Identification of Orphan Receptors

Transforming Growth Factor (TGF)-b Signalling

Contact: John Zwaagstra
Tel.: (514) 496-6384
E-mail: john.zwaagstra@cnrc-nrc.gc.ca

TGF-b is a member of a large family of signalling molecules consisting of more than 40 closely related members. TGF-b signals through the type I (TbRI) and type II (TbRII) receptor. Even though TGF-b inhibits epithelial cell proliferation, thereby playing the role of a tumour suppressor, it has become evident that TGF-b can also promote tumour progression by enhancing tumour invasion and metastasis through a process known as an epithelial to mesenchymal transition (EMT). The group is interested in various aspects of TGF-b's mode of action and has been successful at various levels:

• The ligand binding domains of the TbR's have been mapped using site-directed mutagenesis and biomolecular modeling.
• The kinetics of the ligand-receptor interactions was determined using the SPR-based biosensor.
• Transcriptome analysis of the TGF-b-induced EMT in mouse mammary epithelial cells has generated a list of potential gene targets.

Currently, the group is studying the internalization and intracellular processing of the TbR's, and the consequences of this on the signalling process, and is developing functional assays to monitor these events.

Epidermal Growth Factor (EGF) Signalling

Contact: Maria Jaramillo
Tel.: (514) 496-6384
E-mail: maria.jaramillo@cnrc-nrc.gc.ca

The epidermal growth factor (EGF) receptor (EGFR or erbB-1) belongs to a family of tyrosine kinase receptors that also includes the ErbB-2, ErbB-3 and ErbB-4 receptors. Over-expression of EGFR can be observed in a variety of epithelial tumours and is correlated with poor clinical prognosis in colon, breast and lung cancer. The group is in the process of identifying tumour phenotypic and genotypic profiles that lead to sensitivity to EGFR inhibitors. In addition to tyrosine kinase inhibitors, the mAb 225, which blocks ligand binding and inhibits EGFR, will be tested. In this regard, pathway inhibition, EGFR localization and transcription profiles in breast cancer cell lines and xenograft models will also be analyzed. The group has shown that the 225 mAb confers changes in pathway signalling and EGF receptor subcellular localization in lung adenocarcinoma cell lines, which may contribute to its clinical efficacy. The transcriptional profiles arising from EGFR inhibitor-sensitive versus insensitive preclinical models will be compared with those arising from clinical trails in order to look for biological markers of responsiveness to EGFR-targeted therapeutics.

Identification of Orphan Receptors

Contact: Suzanne Grothé
Tel.: (514) 496-6322
E-mail: suzanne.grothe@cnrc-nrc.gc.ca

The Receptors, Signalling and Proteomics group has a wealth of experience in using the SPR biosensor. The group is now extending the application of the SPR biosensor from monitoring specific protein-protein interactions to identifying (novel) interactors. The approach chosen is to elute specifically bound analyte from the SPR biosensor surface followed by its identification using tandem mass spectroscopy. This technology is being developed in conjunction with Biacore Corp. for the identification of orphan receptors and ligands.

Related Information

Institutes:

• NRC Biotechnology Research Institute