Biol403 MAP kinase signalling

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1 Biol403 MAP kinase signalling The mitogen activated protein kinase (MAPK) pathway is a signalling cascade activated by a diverse range of effectors. The cascade regulates many cellular activities including proliferation and differentiation. Epidermal growth factor (EGF), and a range of other growth factors, activate MAPKs. The role of MAPKs in the EGF intracellular signalling pathway have been described in Biol220 and are briefly revised here. 1

2 EGF binds to the EGF receptor - a tyrosine kinase-based receptor. Binding of EGF causes the monomeric receptor to dimerize and undergo cross-phosphorylation and activation. The SH2 domain of an adaptor protein Grb-2 (growth-factorreceptor bound protein 2) binds to phosphotyrosine residues of the receptor. Grb-2 recruits Sos (Son of Sevenless). Binding of Sos to Grb-2 stimulates the GRF (guanine nucleotide releasing factor) activity of Sos. Sos binds to Ras and promotes a conformational change that allows exchange of GDP for GTP in Ras. There are 3 isoforms of mammalian Ras H-Ras, K-Ras and N- Ras. At their C-terminals there is a CAAX motif which can be farnesylated causing the localisation of Ras to the plasma membrane (or other internal membranes). Ras possesses an intrinsic GTPase activity that eventually returns the system to an inactive (GDP bound) state. This activity is augmented by GAPs (GTPase activating proteins). Activation of Ras leads to the activation of the MAP kinase cascade. 2

3 The ser/thr protein kinase Raf is activated by direct interaction with Ras. Activated Raf phosphorylates a protein known as MEK (MAPK/ERK kinase) at specific ser and thr residues. Activated MEK1 and MEK2 phosphorylate a family of proteins known as MAP kinases (mitogenactivated protein) or ERKs (extracellular-signal regulated protein kinases). Significantly, these phosphorylations occur at tyr and thr residues i.e. MEK shows dual specificity. Activated ERK1 and ERK2 migrate from the cytosol to the nucleus, where they phosphorylate, and activate, a variety of transcription factors including c-jun, c-fos and c-myc. 3

4 Five distinct groups of MAPKs have been identified in mammals: The MEK/ERK cascade ( as described above); The JNK pathway; The p38 pathway; ERK5 (also known as big MAPK 1 it is twice the size of typical MAPKs) and ERK3 (an atypical MAPK) pathways. 4

5 The JNK pathway The major activators of this pathway are cytokines, certain G- protein coupled receptors and cell stress. JNKs control apoptosis and development of cells of the immune system. The c-jun N- terminal kinase (JNK) family contains three isoforms (JNK1, JNK2 and JNK3). JNK is phosphorylated by either MEK4 or MEK7 which are themselves phosphorylated by several protein kinases including MEKK1-4, MLK2-3 and DLK. Once phosphorylated JNK is translocated to the nucleus where it phosphorylates several transcription factors including c- Jun, ATF-2, STAT3 and HSF-1. The p38 pathway There are 4 members of the p38 kinase family α, β γ and δ. Cytokines, hormones, G-protein coupled receptors and cell stress (e.g. heat or osmotic shock) all stimulate this pathway. p38 kinases are targets for both MEK3 and MEK6 and have many substrates including MAPK interacting kinases (Mnk) 1 and 2 and eukaryotic initiation factor 4e. The pathway regulates angiogenesis, cell proliferation, inflammation and cytokine production. 5

6 Scaffolds The role of scaffolds is to provide spatial and temporal organisation of MAPK pathways. Scaffolds bind multiple components of the cascade bringing them into close proximity and thereby ensuring efficient propagation of signalling information. A number of MAPK cascade scaffold proteins have now been identified in mammalian cells. These are a diverse group of proteins, likely to have evolved separately, but related in that they are composed of multiple modular interaction domains or motifs. Ste5 One of the first scaffold proteins to be discovered was Ste5 from yeast. This protein, with no apparent catalytic activity, is required for the mating pathway in Saccharomyces cerevisae. In a-type cells, the α-factor binds a G-protein coupled receptor. Ste-5 is then recruited to the cell membrane where it binds all three kinase components of the mating MAPK module (Ste11, Ste7, Fus3). Ste5 clearly promotes signalling by enforcing proximity of these components. In addition, there is allosteric activation of Fus3 by Ste5 and an alternative interaction between Fus3 and Ste5 makes Fus3 more susceptible to allosteric activation by Ste7. This latter interaction is important in that it ensures that Ste7, which also activates another MAPK (Kss1) involved in a different pathway, activates the mating-specific Fus3 MAPK only when it is bound to Stre5. 6

7 In response to the presence of pheromone (α-factor), Ste20 is activated at the cell membrane and in turn activates Ste11. This initiates a cascade of phosphorylation events leading to the activation and release of Fus3 from the Ste5 scaffold. By spatially coordinating the kinases involved in the pheromone response, Ste5 ensures both the speed and accuracy of signalling. Kinase suppressor of Ras (KSR) KSR was originally assumed to be a kinase; however, activity has not been conclusively demonstrated and it appears, instead, to be MAPK scaffold. Following stimulation by growth factors, KSR translocates from the cytosol to the plasma membrane, where it forms a docking platform for cascade components. Specifically, it binds C-Raf, MEK1/2 and ERK1/2. MEK is constitutively bound to KSR but ERK only binds in response to a stimulus. 7

8 The proteins of this complex are potentially important drug targets - activating mutations is Ras are found in ~ 25% of all human tumours. Drugs that inhibit Raf e.g. sorafenib are used to treat renal and hepatic carcinomas. Such drugs must target Raf only in the context of the KSR-a scaffold if they are to have therapeutic potential. Sorofenib IQGAP1 IQGAP1 is a large, widely expressed protein that regulates many signalling pathways. With several domains it is able to bind multiple proteins (including cytoskeletal elements) among which are components of the MAPK cascade: B-Raf, MEK1, MEK2, ERK1 and ERK2. Although the association between ERK and IQGAP1 is constitutive, the binding of MEK1 only occurs in the presence of stimulus (EGF) whereas the binding of MEK2 is inhibited in the presence of EGF. This may provide an explanation for the observation that MEK1 promotes cellular proliferation whereas MEK2 promotes cellular differentiation. 8

9 β-arrestins β-arrestins are well established regulators of G-protein coupled receptors (causing dissociation of heterotrimeric G proteins). They also directly regulate MAPK cascades. In response to activation of protease activated receptor (PAR), β- arrestin recruits RAF, MEK and ERK to the receptor, enhancing activation of ERK. The complexes accompany the receptor to early endosomes thereby preventing the translocation of active ERK to the nucleus, restricting its activity to cytosolic substrates. Similar expression to FGF (Sef) Sef apparently captures MEK/ERK complexes at the Golgi and inhibits nuclear localisation of ERK, restricting ERK activity to cytosolic substrates (Sef is actually interleukin-17 receptor D). 9

10 Summary of the role of MAPK scaffold proteins in the spatial and temporal organisation of the signalling cascade. Rapid ERK activation via PK-C or Src is transient and allows ERK translocation to the nucleus. Sustained ERK activation is via an endosomal β-arrestin dependent process that confines signalling to the cytosol. Scaffolds and MAPK specificity An aspect of MAPK signalling that is poorly understood is how a particular stimulus elicits the correct response (i.e. MAPK specificity). Given the diverse range of cellular responses induced by numerous different activators, all of which signal through the MEK/ERK pathway, this is a significant issue. Scaffolds are able to control many aspects of MAPK signalling. By bringing together individual components of the cascade, scaffolds facilitate their interactions and propagation of the signal. The scaffold also effectively insulate these components from other signalling pathways i.e. scaffolds can lead to preferential activation and inhibition of signalling cascades. Scaffolds that interact with, or are regulated by, different signalling pathways will allow cross-talk between signalling cascades. 10

11 Summary The mitogen activated protein kinase (MAPK) pathway is a signalling cascade that regulates many cellular activities including proliferation and differentiation. Five distinct groups of MAPKs have been identified in mammals the MEK/ERK cascade, the JNK pathway, the p38 pathway and ERK5/ERK3 pathways. Protein scaffolds bind multiple components of the cascades bringing them into close proximity and thereby ensuring efficient propagation of signalling information. Scaffolds provide spatial and temporal organisation of MAPK pathways and provide an explanation for the specificity of MAPK signalling pathways. References Brown, M. D. & Sacks, D. B. (2009) Cellular Signalling 21, protein scaffolds in MAPK signalling. Alexa, A et al., (2010) FEBS J. 277, Scaffold proteins. Wimmer, R & Baccarini, M. (2010) Trends Biochem. Sci. 35, protein interactions in MAPK signalling. Kiel, C., & Serrano, L. (2012) Curr. Opin. Biotech. 23, MAPK signalling. Drew, B. A. et al., (2012) Biochim. Biophys. Acta 1825, MEK5/ERK5 pathway. 11

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