Burgering group: Signal Transduction
Group leader: Boudewijn M.T. Burgering (about group leader)
Small GTPases of the Ras family are molecular switches that function is guiding extracellular signals towards cellular responses. Our group is studying three of its members, Ras, Rap1 and Ral. Ras, the best-studied member of the family, functions in the control of cell proliferation, cell differentiation and cell death. Rap1 may play a role in the control of the internal organisation of the cell and Ral in the controling vesicular transport systems. PKB is a serine-threonine kinase, which plays a role in regulating growth factor-induced metabolic processes and in regulating cell survival. Our aim is to determine the function and molecular mechanisms of the signalling pathways in which Ras family members and PKB are involved.
The protein kinase B pathway
PKB is a downstream target of PI-3 kinase and as such a downstream element of Ras-mediated signalling. However, most extracellular signals can activate this pathway independently of Ras as well. PKB obtained worldwide attention by the discovery that this kinase is the main mediator of survival signals responsible for the protection of cells for death by apoptosis. In addition, PKB mediates signals, such as those induced by insulin, that regulate cell metabolism. Our research is focussed on establishing substrates for this kinase. First, we found that two other kinases are phosphorylated and regulated by PKB: p70S6 kinase and GSK-3. Very recently, PKB was found to phosphorylate and inactivate the transcription factor AFX, providing an interesting connection with the RalGEF-Ral pathway. This transcription factor is most likely involved in the regulation of metabolic processes. In the near future we will continue our search of novel elements involved in PKB-mediated signalling and to identify the relevant genes that are regulated by the AFX transcription factor.