There are three Ras isoforms in mammals, namely H-Ras, K-Ras and N-Ras. Consequently, Ras GEFs increase Ras activity. In contrast to GAPs, GEFs facilitate the exchange of GDP for GTP, increasing the pool of GTP-bound Ras. Consequently, Ras GAPs act as “off” switches and reduce Ras activity. GAPs reduce the pool of GTP bound Ras by increasing the intrinsic GTPase activity of Ras (and therefore the rate of GTP hydrolysis). This control is provided by two different classes of proteins, GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Regulation of the GTP/GDP bound state of Ras provides tight control over its activity. GTP-Ras activates downstream effectors (see below), which propagate signalling. Ras is a GTPase, which hydrolyses guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Relocation to the membrane activates Sos, which in turn activates Ras. One of these SH2-containing proteins, Grb2, is constitutively bound to the Ras activator Sos, and normally localises to the cytosol. Proteins that contain SH2 (Src homology 2) domains are recruited to the receptors and bind to specific phosphotyrosine residues. Briefly, when growth factors bind to their cognate receptors, the receptors undergo dimerisation, inducing phosphorylation by intrinsic tyrosine kinases. This pathway is activated by protein tyrosine kinase receptors, such as EGF receptor (EGFR) or VEGF receptor (VEGFR). The best characterised of the MAPK pathways is the MEK/ERK cascade. In this review, we focus on the role of protein scaffolds in the modulation of MAPK signalling. Several excellent publications have addressed general MAPK functions. The MAPKs can control events both in the nucleus, such as gene regulation, and extra-nuclear events, such as cytoskeletal reorganisation, through phosphorylation and activation of targets in the cytosol and nucleus. These are MAPK/ERK kinase/extracellular regulated kinase (MEK/ERK), c-Jun N-terminal kinase (JNK), p38, ERK5 and ERK3. Five distinct groups of MAPKs have been identified in mammals. Cells are stimulated by these factors and respond to changes in their environment through manipulation of MAPK signalling. Several growth factors, such as epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), insulin, neurotrophins, and inflammatory cytokines, activate MAPKs. The mitogen activated protein kinase (MAPK) pathway is an intracellular signalling cascade, activated by diverse external cues, that regulates many cellular functions including cell proliferation and differentiation. Protein scaffolds, therefore, are integral elements in the modulation of the MAPK network in fundamental physiological processes. Studies conducted on different scaffolds, in different biological systems, have shown that scaffolds exert substantial control over MAPK signalling, influencing the signal intensity, time course and, importantly, the cellular responses. Key to this control are protein scaffolds, which are multidomain proteins that interact with components of the MAPK cascade in order to assemble signalling complexes. This specificity is achieved by several mechanisms, including temporal and spatial control of MAPK signalling components. Therefore, cells have developed mechanisms by which this single pathway modulates numerous cellular responses from a wide range of activating factors. Diverse cellular functions, ranging from differentiation and proliferation to migration and inflammation, are regulated by MAPK signalling. The mitogen-activated protein kinase (MAPK) pathway allows cells to interpret external signals and respond in an appropriate way.
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