Figure 1

Signalling pathways: general principles. Followed by communication of the signal to different cellular compartments are signal processing and amplification by plasma membrane proximal events. The activation of multiple signal cascades by receptors, different protein post-translational modifications (PTMs), crosstalk between signalling pathways and feedback loops to ensure optimal signalling output are involved in this process. The binding of receptor Tyr kinases (RTKs) to their cognate ligands at the cell surface results in receptor dimerization and autophosphorylation. Phosphorylated Tyr residues subsequently serve as docking sites to recruit signalling mediators, such as growth factor receptor-bound protein 2 (GRB2). Multiple signalling cascades such as the phosphoinositide-3 kinase (PI3K)-AKT, Ras-Raf- extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription (STAT) pathways are activated by the assembly of these signalling complexes. Casitas B-lineage lymphoma (CBL)-mediated ubiquitylation of RTKs controls their endocytosis and the duration of receptor signalling. In addition, binding of tumour necrosis factor-α (TNFα) to its receptor, TNFR1, induces trimerization of the receptor and recruitment of the adaptor protein TNFR1-associated death domain (TRADD) This functions as a hub to assemble a multiprotein signalling complex containing TNFR-associated factor 2 (TRAF2), receptor interacting Ser/Thr protein kinase 1 (RIPK1) and nuclear factor-κB (NF-κB) essential modulator (NEMO). The result is the activation of different signalling networks, such as the ERK MAPK, p38 MAPK and NF-κB pathways. Proteins in the MAPK signalling pathways are activated by both RTKs and TNFα, which allows cells to integrate multiple signals. [Dotted lines indicate indirect activation of signalling pathways or translocation of proteins into the nucleus. IκB, inhibitor of NF-κB; IKK, inhibitor of NF-κB kinase; JNK1, Jun N-terminal kinase 1; MEK, MAPK ERK kinase; mTOR, mammalian target of rapamycin; p70S6K, p70 ribosomal S6 kinase-α; RSK, ribosomal protein S6 kinase-α].