The Mekerk Cascade

The MEK/ERK cascade, the best characterised of the MAPK pathways, is activated in response to protein tyrosine kinase receptors, such as EGF receptor (EGFR) or VEGF receptor (VEGFR) (Pearson et al. 2001). Growth factor binding induces receptor dimerisation and phosphorylation of the cognate receptor by intrinsic tyrosine

Fig. 1 The MAPK signalling cascades. The MAPK networks and pathways are stimulated in response to a variety of external cues. The five families of MAPK, MEK/ERK, JNK, p38, ERK5 and ERK3, are induced by stimuli such as growth factors, cytokines and stress. Although these pathways can be activated by different environmental conditions, crosstalk occurs, enabling this complex network to control cellular behaviour. Adapted from (Raman and Cobb 2003). MAPKKK, MAPK kinase kinase; MAPKK, MAPK kinase; ERK, extracellular regulated kinase; MEK, MAPK/ERK kinase; JNK, c-Jun N-terminal kinase; MEKK, mitogen ERK kinase kinase; DLK, dual leucine zipper-bearing kinase; MLK2, mixed lineage kinase; TAO, thousand-and-one amino acids; TAK, transforming growth factor-beta-activated kinase

Fig. 1 The MAPK signalling cascades. The MAPK networks and pathways are stimulated in response to a variety of external cues. The five families of MAPK, MEK/ERK, JNK, p38, ERK5 and ERK3, are induced by stimuli such as growth factors, cytokines and stress. Although these pathways can be activated by different environmental conditions, crosstalk occurs, enabling this complex network to control cellular behaviour. Adapted from (Raman and Cobb 2003). MAPKKK, MAPK kinase kinase; MAPKK, MAPK kinase; ERK, extracellular regulated kinase; MEK, MAPK/ERK kinase; JNK, c-Jun N-terminal kinase; MEKK, mitogen ERK kinase kinase; DLK, dual leucine zipper-bearing kinase; MLK2, mixed lineage kinase; TAO, thousand-and-one amino acids; TAK, transforming growth factor-beta-activated kinase kinases. Tyrosine phosphorylation of the receptor induces recruitment of proteins that contain SH2 (Src homology 2) domains, including the adaptor protein Grb2. Grb2 is constitutively bound to the Ras activator Sos and is normally localised to the cytosol. This relocation activates Sos, which in turn activates Ras. Ras is a GTPase and hydrolyses guanosine triphosphate (GTP) to guanosine diphosphate (GDP) (Fig. 2). When bound to GTP, Ras is able to bind to, and activate, downstream effectors, allowing propagation of signalling. Therefore, by regulating the GTP/GDP-bound state of Ras, cells have tight control over its activity. Two classes of proteins provide this control. GTPase-activating proteins (GAPs) upregulate the intrinsic GTPase activity of Ras (and therefore the rate of GTP hydrolysis), reducing the pool of GTP-bound Ras. Consequently, Ras GAPs act as "off' switches and reduce Ras activity. Guanine-nucleotide exchange factors (GEFs), in contrast, promote the exchange of GDP for GTP, increasing the pool of GTP-bound Ras, thereby increasing Ras activity. Mammalian cells contain three Ras isoforms, H-Ras, K-Ras and N-Ras. At their C-terminal ends, Ras proteins contain a CAAX motif, in which a cysteine (C) is followed by two aliphatic amino acids (A) and any other amino acid (X). This motif is farnesylated by farnesyl transferase, resulting in membrane localisation of Ras GTPases (Mor and Philips 2006).

When GTP bound, Ras recruits the kinase Raf to the membrane, where is becomes active. There are three known isoforms of Raf, namely A-Raf, B-Raf and C-Raf (also termed Raf-1). The Raf proteins share common architecture and all function as serine/threonine kinases, but have distinct functions (Wellbrock et al. 2004). Raf catalyses the phosphorylation and activation of the dual specificity kinases, MAPK/ERK kinase 1 and 2 (MEK1 and MEK2), which in turn activate extracellular regulated kinases, ERK1 and ERK2 (Fig. 2). Once active, ERKs dimerise and either translocate to the nucleus, where they phosphorylate transcription factors, such as the Ets family, or remain in the cytosol, where they catalyse the phosphorylation of substrates in multiple cellular compartments (Fig. 2) (reviewed in Roux and Blenis 2004). The predominant sequelae of MEK/ERK signalling are proliferation and differentiation.

Fig. 2 The MEK/ERK pathway. Growth factors, such as EGF, PDGF and NGF, induce the exchange of GDP for GTP on Ras, thereby activating Ras. GTP-Ras activates the Raf kinases, which then phosphorylate the downstream targets, MEK1 and MEK2. MEK1/2 in turn phospho-rylates ERK1 and ERK2, which activate cytosolic and nuclear substrates by catalysing their phosphorylation

Fig. 2 The MEK/ERK pathway. Growth factors, such as EGF, PDGF and NGF, induce the exchange of GDP for GTP on Ras, thereby activating Ras. GTP-Ras activates the Raf kinases, which then phosphorylate the downstream targets, MEK1 and MEK2. MEK1/2 in turn phospho-rylates ERK1 and ERK2, which activate cytosolic and nuclear substrates by catalysing their phosphorylation

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