PDGF receptors are key cell surface sensors that regulate the growth and migration of mesenchymal cells in all organs. Alterations of PDGF receptor genes (PDGFRA and PDGFRB) have been associated to a variety of human pathologies, including cancer, leukemia, brain calcification, aneurysms and congenital disorders such as Penttinen and Kosaki syndromes. Understanding how mutations of these two genes can lead to such an array of different diseases in not only a fascinating fundamental quest but also the key to finding cures for these debilitating pathological conditions.
The Demoulin laboratory is the reference center for testing PDGF receptor variants. Gene alterations are identified using next generation sequencing technologies. The team has developed multiple assays to assess the impact of PDGFRA and PDGFRB mutations in cell culture. The sensitivity to tyrosine kinase inhibitors is also tested in vitro. The team benefits from a network of collaborations with clinicians, pathologists and geneticists.
PDGF receptors signal by phosphorylating intracellular proteins on tyrosines. This leads to the activation of signaling enzymes (e.g. phosphatidylinositol-3 kinase, phospholipase Cγ, AKT, ERK…) and transcription factors (e.g. STAT1, STAT3, STAT5, SRF, SREBP1). This process is studied using phospho-proteomics and RNA sequencing. Receptor mutations associated with distinct diseases can lead to either a gain or a loss specific signaling pathways.