Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling.

The mitogen activated protein (MAP) kinase module: (Raf -->MEK-->ERKs) is central to the control of cell growth, cell differentiation and cell survival. The fidelity of signalling and the spatio-temporal activation are key determinants in generating precise biological responses. The fidelity is ensured by scaffold proteins - protein kinase 'insulators' - and by specific docking sites. The duration and the intensity of the response are in part controlled by the compartmentalization of the signalling molecules. Growth factors promote rapid nuclear translocation and persistent activation of p42/p44 MAP kinases, respectively and ERK2/ERK1, during the entire G1 period with an extinction during the S-phase. These features are exquisitely controlled by the temporal induction of the MAP kinase phosphatases, MKP1-3. MKP1 and 2 induction is strictly controlled by the activation of the MAP kinase module providing evidence for an auto-regulatory mechanism. This negative regulatory loop is further enhanced by the capacity of p42/p44 MAPK to phosphorylate MKP1 and 2. This action reduces the degradation rate of MKPs through the ubiquitin-proteasomal system. Whereas the two upstream kinases of the module (Raf and MEK) remain cytoplasmic, ERKs (anchored to MEK in the cytoplasm of resting cells) rapidly translocate to the nucleus upon mitogenic stimulation. This latter process is rapid, reversible and controlled by the strict activation of the MAPK cascade. Following long-term MAPK stimulation, p42/p44 MAPKs progressively accumulate in the nucleus in an inactive form. Therefore we propose that the nucleus represents a site for ERK action, sequestration and signal termination. With the generation of knockdown mice for each of the ERK isoforms, we will illustrate that besides controlling cell proliferation the ERK cascade also controls cell differentiation and cell behaviour.