George Mavrothalassitis

Our long standing interest is the signal regulated transcriptional control in development and disease. Specifically the ETS genes within the RTK/ras/erk pathway in normal and tumor development. For the last several years we have explored multiple facets of the ERF transcription factor as a paradigm of signal-regulated transcriptional control.
We studied the mechanism of ERF regulation by Erks, and established that a unique protein-protein interaction determines its phosphorylation. We determined that this phosphorylation leads to its regulation as a transcription factor by dictating its sub-cellular compartmentalisation. We studied ERF function as a tumor suppressor and we established that it can repress cell proliferation via an Rb-dependent pathway while specific Erk-regulation resistent mutations can be effective against ras-induced tumorigenesis. We also showed that cat affect epithelial-to -mesenchymal-transition (EMT) via semaphoring regulation. We further studied its function in the context of the whole animal and found that the loss of Erf leads to embryonic lethality as a result of extensive proliferation and defective differentiation of the trophoblast stem cell. Recently we determined that the ERF haploinsuficiency leads to craniosynistosis in mouse and humans.
Our work led to the hypothesis that “signaling pathways also signal quantitatively their inactive state through inhibitors/repressors” which we are exploring in diverse disease related systems.