Pathway: MAPK6/MAPK4 signaling
Reactions in pathway: MAPK6/MAPK4 signaling :
MAPK6/MAPK4 signaling
MAPK6 and MAPK4 (also known as ERK3 and ERK4) are vertebrate-specific atypical MAP kinases. Atypical MAPK are less well characterized than their conventional counterparts, and are generally classified as such based on their lack of activation by MAPKK family members. Unlike the conventional MAPK proteins, which contain a Thr-X-Tyr motif in the activation loop, MAPK6 and 4 have a single Ser-Glu-Gly phospho-acceptor motif (reviewed in Coulombe and Meloche, 2007; Cargnello et al, 2011). MAPK6 is also distinct in being an unstable kinase, whose turnover is mediated by ubiquitin-dependent degradation (Coulombe et al, 2003; Coulombe et al, 2004). The biological functions and pathways governing MAPK6 and 4 are not well established. MAPK6 and 4 are phosphorylated downstream of class I p21 activated kinases (PAKs) in a RAC- or CDC42-dependent manner (Deleris et al, 2008; Perander et al, 2008; Deleris et al, 2011; De La Mota-Peynado et al, 2011). One of the only well established substrates of MAPK6 and 4 is MAPKAPK5, which contributes to cell motility by promoting the HSBP1-dependent rearrangement of F-actin (Gerits et al, 2007; Kostenko et al, 2009a; reviewed in Kostenko et al, 2011b). The atypical MAPKs also contribute to cell motility and invasiveness through the NCOA3:ETV4-dependent regulation of MMP gene expression (Long et al, 2012; Yan et al, 2008; Qin et al, 2008). Both of these pathways may be misregulated in human cancers (reviewed in Myant and Sansom, 2011; Kostenko et al, 2012)
The mitogen activated protein kinases (MAPKs) are a family of conserved protein serine threonine kinases that respond to varied extracellular stimuli to activate intracellular processes including gene expression, metabolism, proliferation, differentiation and apoptosis, among others.
The classic MAPK cascades, including the ERK1/2 pathway, the p38 MAPK pathway, the JNK pathway and the ERK5 pathway are characterized by three tiers of sequentially acting, activating kinases (reviewed in Kryiakis and Avruch, 2012; Cargnello and Roux, 2011). The MAPK kinase kinase kinase (MAPKKK), at the top of the cascade, is phosphorylated on serine and threonine residues in response to external stimuli; this phosphorylation often occurs in the context of an interaction between the MAPKKK protein and a member of the RAS/RHO family of small GTP-binding proteins. Activated MAPKKK proteins in turn phosphorylate the dual-specificity MAPK kinase proteins (MAPKK), which ultimately phosphorylate the MAPK proteins in a conserved Thr-X-Tyr motif in the activation loop.
Less is known about the activation of the atypical families of MAPKs, which include the ERK3/4 signaling cascade, the ERK7 cascade and the NLK cascade. Although the details are not fully worked out, these MAPK proteins don't appear to be phosphorylated downstream of a 3-tiered kinase system as described above (reviewed in Coulombe and Meloche, 2007; Cargnello and Roux, 2011) .
Both conventional and atypical MAPKs are proline-directed serine threonine kinases and, once activated, phosphorylate substrates in the consensus P-X-S/T-P site. Both cytosolic and nuclear targets of MAPK proteins have been identified and upon stimulation, a proportion of the phosphorylated MAPKs relocalize from the cytoplasm to the nucleus. In some cases, nuclear translocation may be accompanied by dimerization, although the relationship between these two events is not fully elaborated (reviewed in Kryiakis and Avruch, 2012; Cargnello and Roux, 2011; Plotnikov et al, 2010).
The classic MAPK cascades, including the ERK1/2 pathway, the p38 MAPK pathway, the JNK pathway and the ERK5 pathway are characterized by three tiers of sequentially acting, activating kinases (reviewed in Kryiakis and Avruch, 2012; Cargnello and Roux, 2011). The MAPK kinase kinase kinase (MAPKKK), at the top of the cascade, is phosphorylated on serine and threonine residues in response to external stimuli; this phosphorylation often occurs in the context of an interaction between the MAPKKK protein and a member of the RAS/RHO family of small GTP-binding proteins. Activated MAPKKK proteins in turn phosphorylate the dual-specificity MAPK kinase proteins (MAPKK), which ultimately phosphorylate the MAPK proteins in a conserved Thr-X-Tyr motif in the activation loop.
Less is known about the activation of the atypical families of MAPKs, which include the ERK3/4 signaling cascade, the ERK7 cascade and the NLK cascade. Although the details are not fully worked out, these MAPK proteins don't appear to be phosphorylated downstream of a 3-tiered kinase system as described above (reviewed in Coulombe and Meloche, 2007; Cargnello and Roux, 2011) .
Both conventional and atypical MAPKs are proline-directed serine threonine kinases and, once activated, phosphorylate substrates in the consensus P-X-S/T-P site. Both cytosolic and nuclear targets of MAPK proteins have been identified and upon stimulation, a proportion of the phosphorylated MAPKs relocalize from the cytoplasm to the nucleus. In some cases, nuclear translocation may be accompanied by dimerization, although the relationship between these two events is not fully elaborated (reviewed in Kryiakis and Avruch, 2012; Cargnello and Roux, 2011; Plotnikov et al, 2010).
Signal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such as hormones and growth factors, or reacting to other types of stimuli, such as light. Stimulation of transmembrane receptors leads to their conformational change which propagates the signal to the intracellular environment by activating downstream signaling cascades. Depending on the cellular context, this may impact cellular proliferation, differentiation, and survival. On the organism level, signal transduction regulates overall growth and behavior.
Receptor tyrosine kinases (RTKs) transmit extracellular signals by phosphorylating their protein partners on conserved tyrosine residues. Some of the best studied RTKs are EGFR (reviewed in Avraham and Yarden, 2011), FGFR (reviewed in Eswarakumar et al, 2005), insulin receptor (reviewed in Saltiel and Kahn, 2001), NGF (reviewed in Reichardt, 2006), PDGF (reviewed in Andrae et al, 2008) and VEGF (reviewed in Xie et al, 2004). RTKs frequently activate downstream signaling through RAF/MAP kinases (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT (reviewed in Manning and Cantley, 2007) and PLC- gamma (reviewed in Patterson et al, 2005), which ultimately results in changes in gene expression and cellular metabolism.
Receptor serine/threonine kinases of the TGF-beta family, such as TGF-beta receptors (reviewed in Kang et al. 2009) and BMP receptors (reviewed in Miyazono et al. 2009), transmit extracellular signals by phosphorylating regulatory SMAD proteins on conserved serine and threonine residues. This leads to formation of complexes of regulatory SMADs and SMAD4, which translocate to the nucleus where they act as transcription factors.
WNT receptors transmit their signal through beta-catenin. In the absence of ligand, beta-catenin is constitutively degraded in a ubiquitin-dependent manner. WNT receptor stimulation releases beta-catenin from the destruction complex, allowing it to translocate to the nucleus where it acts as a transcriptional regulator (reviewed in MacDonald et al, 2009 and Angers and Moon, 2009). WNT receptors were originally classified as G-protein coupled receptors (GPCRs). Although they are structurally related, GPCRs primarily transmit their signals through G-proteins, which are trimers of alpha, beta and gamma subunits. When a GPCR is activated, it acts as a guanine nucleotide exchange factor, catalyzing GDP to GTP exchange on the G-alpha subunit of the G protein and its dissociation from the gamma-beta heterodimer. The G-alpha subunit regulates the activity of adenylate cyclase, while the gamma-beta heterodimer can activate AKT and PLC signaling (reviewed in Rosenbaum et al. 2009, Oldham and Hamm 2008, Ritter and Hall 2009).
NOTCH receptors are activated by transmembrane ligands expressed on neighboring cells, which results in cleavage of NOTCH receptor and release of its intracellular domain. NOTCH intracellular domain translocates to the nucleus where it acts as a transcription factor (reviewed in Kopan and Ilagan, 2009).
Integrins are activated by extracellular matrix components, such as fibronectin and collagen, leading to conformational change and clustering of integrins on the cell surface. This results in activation of integrin-linked kinase and other cytosolic kinases and, in co-operation with RTK signaling, regulates survival, proliferation and cell shape and adhesion (reviewed in Hehlgans et al, 2007) .
Besides inducing changes in gene expression and cellular metabolism, extracellular signals that trigger the activation of Rho GTP-ases can trigger changes in the organization of cytoskeleton, thereby regulating cell polarity and cell-cell junctions (reviewed in Citi et al, 2011).
Receptor tyrosine kinases (RTKs) transmit extracellular signals by phosphorylating their protein partners on conserved tyrosine residues. Some of the best studied RTKs are EGFR (reviewed in Avraham and Yarden, 2011), FGFR (reviewed in Eswarakumar et al, 2005), insulin receptor (reviewed in Saltiel and Kahn, 2001), NGF (reviewed in Reichardt, 2006), PDGF (reviewed in Andrae et al, 2008) and VEGF (reviewed in Xie et al, 2004). RTKs frequently activate downstream signaling through RAF/MAP kinases (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT (reviewed in Manning and Cantley, 2007) and PLC- gamma (reviewed in Patterson et al, 2005), which ultimately results in changes in gene expression and cellular metabolism.
Receptor serine/threonine kinases of the TGF-beta family, such as TGF-beta receptors (reviewed in Kang et al. 2009) and BMP receptors (reviewed in Miyazono et al. 2009), transmit extracellular signals by phosphorylating regulatory SMAD proteins on conserved serine and threonine residues. This leads to formation of complexes of regulatory SMADs and SMAD4, which translocate to the nucleus where they act as transcription factors.
WNT receptors transmit their signal through beta-catenin. In the absence of ligand, beta-catenin is constitutively degraded in a ubiquitin-dependent manner. WNT receptor stimulation releases beta-catenin from the destruction complex, allowing it to translocate to the nucleus where it acts as a transcriptional regulator (reviewed in MacDonald et al, 2009 and Angers and Moon, 2009). WNT receptors were originally classified as G-protein coupled receptors (GPCRs). Although they are structurally related, GPCRs primarily transmit their signals through G-proteins, which are trimers of alpha, beta and gamma subunits. When a GPCR is activated, it acts as a guanine nucleotide exchange factor, catalyzing GDP to GTP exchange on the G-alpha subunit of the G protein and its dissociation from the gamma-beta heterodimer. The G-alpha subunit regulates the activity of adenylate cyclase, while the gamma-beta heterodimer can activate AKT and PLC signaling (reviewed in Rosenbaum et al. 2009, Oldham and Hamm 2008, Ritter and Hall 2009).
NOTCH receptors are activated by transmembrane ligands expressed on neighboring cells, which results in cleavage of NOTCH receptor and release of its intracellular domain. NOTCH intracellular domain translocates to the nucleus where it acts as a transcription factor (reviewed in Kopan and Ilagan, 2009).
Integrins are activated by extracellular matrix components, such as fibronectin and collagen, leading to conformational change and clustering of integrins on the cell surface. This results in activation of integrin-linked kinase and other cytosolic kinases and, in co-operation with RTK signaling, regulates survival, proliferation and cell shape and adhesion (reviewed in Hehlgans et al, 2007) .
Besides inducing changes in gene expression and cellular metabolism, extracellular signals that trigger the activation of Rho GTP-ases can trigger changes in the organization of cytoskeleton, thereby regulating cell polarity and cell-cell junctions (reviewed in Citi et al, 2011).