tailieunhanh - Báo cáo khoa học: Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling Delivered on 24 October 2002 at the 28th FEBS Meeting in Istanbul

The mitogen activated protein (MAP) kinase module: (Raf fiMEKfiERKs) is central to the control of cell growth, cell differentiation and cell survival. The fidelity of signalling and the spatio-temporal activation are key deter-minants in generating precise biological responses. The fidelity is ensured by scaffold proteins – protein kinase insulators – andby specific docking sites. The duration and the intensity of the response are in part controlled by the compartmentalization of the signalling molecules. . | Eur. J. Biochem. 270 3291-3299 2003 FEBS 2003 doi THE SIR HANS KREBS LECTURE Fidelity and spatio-temporal control in MAP kinase ERKs signalling Delivered on 24 October 2002 at the 28th FEBS Meeting in Istanbul Jacques Pouyssegur and Philippe Lenormand Institute of Signaling Developmental Biology and Cancer Research CNRS-UMR 6543 Centre Antoine Lacassagne Nice France The mitogen activated protein MAP kinase module Raf fi MEK fi 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 longterm MAPK stimulation p42 p44 MAPKs progressively accumulate in the nucleus in an inactive form. Therefore we propose that the nucleus