Stimulation of cells by many extracellular agents results in a massive and rapid nuclear translocation of up to 80 distinct signaling proteins important for the regulation of stimulated transcription. We have previously shown that this translocation is not dependent eon the canonical nuclear translocation signals (NLS) or Impα/β, but is rather mediated by the group of ill-studied beta-like importins (imps 2-13), which we found to be important regulators of stimulated transcription. We are now studying the mechanisms by which these importins operate, and already found that each of them may use more than one mechanism. We are also identifying the physiological functions of these importins related to the translocation of signaling proteins, and targeting them for the cure of cancer and inflammation.
Research Projects
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The role of alternatively spliced isoforms of MAPKs in mitosis |
MAPKs are known to respond to a large number of stimuli and to induce many distinct, and even opposing cellular processes. This raises the question as to how could each of these linear cascades determine its specificity upon distinct stimulation. We have shown that one of the mechanisms that allow these diverse functions is the existence of several alternatively spliced forms in each tier of the signaling cascades. For example we showed that a sub-rout of the ERK cascade is composed of the alternatively spliced MEK1b and ERK1c that uniquely regulate Golgi fragmentation. We are currently studying the mechanism of action of this cascade and its function in additional cellular processes. We aim to target this specific ERK route for the cure of cancer and developmental diseases.
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MEK1/2 functions in health and disease |
The MAPKKs MEK1 and MEK2 are dual specificity kinases that are phosphorylate specifically the two regulatory sites of ERK1/2. In addition, we found the MEK1/2 may operate as nuclear export proteins and affect other processes and pathologies by distinct protein-protein interactions. Interestingly, mutations of MEK1/2 were found to induce cellular transformation (oncogenes) as well as the genetic developmental Cardio-Facio-Cutaneous (CFC) syndrome. However, the activity of the mutants is relatively low, and therefore it is not clear how do they operate. We are currently studying the interaction of MEK1/2 and their mutants with various other signaling components, including the central survival factor AKT, and elucidating the mechanism of action of MEK1/2 mutants in cancer and CFC.
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Other projects |
- PP2A switch in the regulation of AKT and JNK by Gq-coupled receptors. We found that Gq activation results in the reduction of AKT activity, which leads to JNK activation and apoptosis. This mechanism is regulated by a PP2A switch that directly affects PI3K and AKT activity. We are currently studying the mechanism by which this PP2A switch operates, and the way it can be used as an anti cancer target.
- Phosphorylated PEDF as a potent anti angiogenic agent. Pigment epithelium-derived factor (PEDF) is a known anti angiogenic agent that operates in the eye as well as in other organs. We found that this agent undergoes three phosphorylations, by CKII and PKA, that strongly elevate its activity. We are now interested in identifying the PEDF receptor and develop it as an anti-angiogenic target in the cure of cancer.
- Activation of the ERK cascade by Non-ionizing radiation. One of the questions in the study of non-ionizing radiation (electromagnetic field; EMF) is whether it may affect cells. We are currently using ERK as a very sensitive readout for the effect of extremely low frequency-EMF on ERK activation, and interested to find out the mechanism by which the radiation is absorbed in the cells (what is the antennae”), and transmitted downstream by the ERK cascade.