Department of Biological Regulation

Weizmann Institute of Science

פרופ' רוני סגר

In my laboratory we are studying all of the above cascades, although our main studies in the last years focused on the extracellular signal-regulated kinase (ERK) cascade. Since ERK activation occurs in response to diverse stimuli, and it can regulate large number of distinct cellular processes, one of the key questions in the field is the determination of the signaling specificity of the ERK cascade. In other words, what are the mechanisms that allow similar ERK activations to result in such a diverse array of downstream effects? In the past years we concentrated on several such mechanisms, including: (i) Compartmentalization and subcellular localization that may direct ERK signals to distinct targets. (ii) The production of alternatively spliced forms of the ERK with distinct substrate specificities. (iii) Crosstalk with other signaling cascades that may modify the signaling outcome. (iv) Regulation of the ERK cascade by phosphatases, which are the tool that governs the duration of the signal and thereby modulate the repertoire of ERK’s targets. Few of our recent findings are:
(a) Subcellular localization: We have previously shown that ERK1/2 and MEK1/2 are localized in the cytosol of resting cells due to interactions with anchoring proteins. Upon activation, ERK1/2 and MEK1/2 are detached from the anchoring proteins and translocate into the nucleus. Immediately after entering the nucleus, MEK1/2 are rapidly exported from this location by CRM1, whereas ERK1/2 are retained in the nucleus for 30-180 minutes. Some of our main findings during this study are: (i) Identification of the regions in ERK1/2 and MEK1/2 that are responsible for each step of the translocation, including cytosolic retention sequence (CRS, also termed CD, Fig. 2). (ii) The cyto-nuclear shuttle of MEK1 may induce an export of nuclear proteins such as PPAR or estrogen-receptor to the cytosol and inhibit their nuclear activity. (iii) The subcellular localization of ERK5-MEK5 is distinct from other MAPK components as they are constantly localized in the nucleus, and their activity is regulated by modulation in intracellular calcium levels.