The MAP kinase signalling pathways (adapted from http://www.sabiosciences.com/).

Structure of the ERK pathway (adapted from http://www.sabiosciences.com/). Upon ligand binding, RTK autophosphorylates on tyrosine residues, which serve as docking sites for adaptor and signalling molecules. Ras is activated by the recruitment of guanosine-nucleotide exchange factors (SOS, C3G) via adaptor proteins (Shc and Grb2; Crk). Ras can activate Raf-1 and B-Raf; Rap1 presumably can activate B-Raf. Raf proteins phosphorylate and activate MEK-1/2, which in turn activate ERK-1/2 (indicated by black arrows).

The JNK signalling pathway (adapted from http://www.sabiosciences.com/). Upstream events are poorly defined, but in the case of growth factors and the cytokine TNF are known to involve G proteins such as Rac and cdc-42 and the protein TRAF2. Activated JNK1 and JNK2 isoforms phosphorylate the AP-1 subunit c-Jun, increasing its transcriptional activity. ASK1, apoptosis signal-stimulating kinase 1; MLK, mixed-lineage protein kinases; TAK1, transforming growth factor-β-activated kinase-1.

The p38 signalling cascade (adapted from http://www.sabiosciences.com/). RNA-binding proteins mediate regulation of cytokine mRNA stability through p38/MK2 signalling. LPS activates p38 MAPK signalling in a variety of cells, leading to transcriptional activation of cytokine genes or enhanced mRNA stability and translation (highlighted areas). The fate of adenine- and uridine- (AU-) rich elements (ARE) mRNA is dependent on the presence of destabilizing and stabilizing mRNA-binding proteins. p38 MAPK activates MK2 in the nucleus, allowing for MK2 translocation to the cytoplasm. MK2 subsequently phosphorylates destabilizing mRNA-binding proteins such as TTP. This action prevents TTP from interacting with ARE cytokines. Simultaneously, activation of the p38 MAPK pathway results in translocation of HuR, a stabilizing RNA-binding protein, from the nucleus to the cytoplasm. Thus, upon p38/MK2 activation and phosphorylation of TTP, cytokine mRNA stability is enhanced, because TTP is no longer dictating mRNA triage and exonuclease decay.

Alternative signaling in the presence of cyclosporine A. In normal, signaling calcineurin binds to and dephosphorylates NFAT, allowing it to enter the nucleus where it induces IL-2 expression. In the presence of cyclosporine this pathway is blocked by the binding of the cyclosporine/cyclophilin complex to calcineurin, which prevents the subsequent binding to NFAT. Alternative signaling occurs via the induction of a MAPK cascade, resulting in the expression of IL-2.