MAP kinase activation (Homo sapiens)

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10, 13, 14, 2619, 251, 5, 6, 11, 15...2, 7, 23, 2512, 194, 9, 242, 7, 232, 17, 2012, 18cytosolnucleoplasmphospho-p38 MAPK :phospho MAPKAPK2 orphospho MaPKAPK3ATPp-S,2T-MAPKAPK3 RAF-independentMAPK1/3 activationp-T180,Y182-MAPK11 p-T180,Y182-MAPK14 MAP3K8MAPK targets/Nuclear eventsmediated by MAPkinasesATPp-MKK3/p-MKK6MKK3/MKK6ATPp-MAPK8/9/10ADPp-S,2T-MAPKAPK3 p-T222,S272,T334-MAPKAPK2 p-T180,Y182-MAPK11 MAPKAPK3 MAPK14 MAPK8/9/10phospho-p38 MAPK:MAPKAPK2/3ADPATPMEK1, SEK1MAPKAPK2 p-MKK3/p-MKK6ADPADPADPATPMAPK11 ATPp-T180,Y182-MAPK11 Activated TAKcomplexesp-T180,Y182-MAPK14 p-MAP2K4/p-MAP2K7MAPKAPK3 MAPKAPK2 p-p38MAPK:p-MAPKAPK2/3MKK4/MKK7ADPp-T222,S272,T334-MAPKAPK2 Phospho-MEK1,phospho-SEK1p-MAPK8/9/10p38 MAPK:MAPKAPK2/3p-T180,Y182-MAPK14 8, 27, 293, 21, 28


Description

The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002).

There are three major groups of MAP kinases

  • the extracellular signal-regulated protein kinases ERK1/2,
  • the p38 MAP kinase
  • and the c-Jun NH-terminal kinases JNK.
<p>ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).<p>MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.<p>The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.<p>The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear. Source:Reactome.</div>

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Bibliography

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History

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114752view16:24, 25 January 2021ReactomeTeamReactome version 75
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99507view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99152view12:41, 31 October 2018ReactomeTeamreactome version 62
93984view13:49, 16 August 2017ReactomeTeamreactome version 61
93588view11:28, 9 August 2017ReactomeTeamreactome version 61
87875view12:14, 25 July 2016RyanmillerOntology Term : 'kinase mediated signaling pathway' added !
87874view12:13, 25 July 2016RyanmillerOntology Term : 'signaling pathway pertinent to immunity' added !
87873view12:12, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86696view09:24, 11 July 2016ReactomeTeamreactome version 56
83420view11:11, 18 November 2015ReactomeTeamVersion54
81623view13:10, 21 August 2015ReactomeTeamVersion53
78712view14:27, 18 January 2015EgonwRemoved @GroupRefs to a that didn't exist in the GPML.
77083view08:38, 17 July 2014ReactomeTeamFixed remaining interactions
76788view12:15, 16 July 2014ReactomeTeamFixed remaining interactions
76111view10:17, 11 June 2014ReactomeTeamRe-fixing comment source
75823view11:38, 10 June 2014ReactomeTeamReactome 48 Update
75173view14:12, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74820view08:55, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated TAK complexesR-HSA-772536 (Reactome)
MAP3K8ProteinP41279 (Uniprot-TrEMBL)
MAPK targets/

Nuclear events mediated by MAP

kinases		PathwayR-HSA-450282 (Reactome) MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity.

The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.

Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).

JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK.

MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
MAPK8/9/10R-HSA-450289 (Reactome)
MAPKAPK2 ProteinP49137 (Uniprot-TrEMBL)
MAPKAPK3 ProteinQ16644 (Uniprot-TrEMBL)
MEK1, SEK1R-HSA-451647 (Reactome)
MKK3/MKK6R-HSA-167916 (Reactome)
MKK4/MKK7R-HSA-450305 (Reactome)
Phospho-MEK1, phospho-SEK1R-HSA-451654 (Reactome)
RAF-independent MAPK1/3 activationPathwayR-HSA-112409 (Reactome) Depending upon the stimulus and cell type mitogen-activated protein kinases (MAPK) signaling pathway can transmit signals to regulate many different biological processes by virtue of their ability to target multiple effector proteins (Kyriakis JM & Avruch J 2012; Yoon and Seger 2006; Shaul YD & Seger R 2007; Arthur JS & Ley SC 2013). In particular, the extracellular signal-regulated kinases MAPK3(ERK1) and MAPK1 (ERK2) are involved in diverse cellular processes such as proliferation, differentiation, regulation of inflammatory responses, cytoskeletal remodeling, cell motility and invasion through the increase of matrix metalloproteinase production (Viala E & Pouyssegur J 2004; Hsu MC et al. 2006; Dawson CW et al.2008; Kuriakose T et al. 2014).The canonical RAF:MAP2K:MAPK1/3 cascade is stimulated by various extracellular stimuli including hormones, cytokines, growth factors, heat shock and UV irradiation triggering the GEF-mediated activation of RAS at the plasma membrane and leading to the activation of the RAF MAP3 kinases. However, many physiological and pathological stimuli have been found to activate MAPK1/3 independently of RAF and RAS (Dawson CW et al. 2008; Wang J et al. 2009; Kuriakose T et al. 2014). For example, AMP-activated protein kinase (AMPK), but not RAF1, was reported to regulate MAP2K1/2 and MAPK1/3 (MEK and ERK) activation in rat hepatoma H4IIE and human erythroleukemia K562 cells in response to autophagy stimuli (Wang J et al. 2009). Tumor progression locus 2 (TPL2, also known as MAP3K8 and COT) is another MAP3 kinase which promotes MAPK1/3 (ERK)-regulated immune responses downstream of toll-like receptors (TLR), TNF receptor and IL1beta signaling pathways (Gantke T et al. 2011).

In response to stimuli the cell surface receptors transmit signals inducing MAP3 kinases, e.g., TPL2, MEKK1, which in turn phosphorylate MAP2Ks (MEK1/2). MAP2K then phosphorylate and activate the MAPK1/3 (ERK1 and ERK2 MAPKs). Activated MAPK1/3 phosphorylate and regulate the activities of an ever growing pool of substrates that are estimated to comprise over 160 proteins (Yoon and Seger 2006). The majority of ERK substrates are nuclear proteins, but others are found in the cytoplasm and other organelles. Activated MAPK1/3 can translocate to the nucleus, where they phosphorylate and regulate various transcription factors, such as Ets family transcription factors (e.g., ELK1), ultimately leading to changes in gene expression (Zuber J et al. 2000).

p-MAP2K4/p-MAP2K7R-HSA-450299 (Reactome)
p-MAPK8/9/10R-HSA-450226 (Reactome)
p-MAPK8/9/10R-HSA-450253 (Reactome)
p-MKK3/p-MKK6R-HSA-167984 (Reactome)
p-MKK3/p-MKK6R-HSA-450343 (Reactome)
p-S,2T-MAPKAPK3 ProteinQ16644 (Uniprot-TrEMBL)
p-T180,Y182-MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
p-T222,S272,T334-MAPKAPK2 ProteinP49137 (Uniprot-TrEMBL)
p-p38 MAPK:p-MAPKAPK2/3ComplexR-HSA-450254 (Reactome)
p38 MAPK:MAPKAPK2/3ComplexR-HSA-450269 (Reactome)
phospho-p38 MAPK :

phospho MAPKAPK2 or

phospho MaPKAPK3		ComplexR-HSA-450241 (Reactome)
phospho-p38 MAPK: MAPKAPK2/3ComplexR-HSA-450213 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-168162 (Reactome)
ADPArrowR-HSA-450222 (Reactome)
ADPArrowR-HSA-450333 (Reactome)
ADPArrowR-HSA-450337 (Reactome)
ADPArrowR-HSA-450346 (Reactome)
ADPArrowR-HSA-451649 (Reactome)
ATPR-HSA-168162 (Reactome)
ATPR-HSA-450222 (Reactome)
ATPR-HSA-450333 (Reactome)
ATPR-HSA-450337 (Reactome)
ATPR-HSA-450346 (Reactome)
ATPR-HSA-451649 (Reactome)
Activated TAK complexesmim-catalysisR-HSA-450337 (Reactome)
Activated TAK complexesmim-catalysisR-HSA-450346 (Reactome)
MAP3K8mim-catalysisR-HSA-451649 (Reactome)
MAPK8/9/10R-HSA-168162 (Reactome)
MEK1, SEK1R-HSA-451649 (Reactome)
MKK3/MKK6R-HSA-450346 (Reactome)
MKK4/MKK7R-HSA-450337 (Reactome)
Phospho-MEK1, phospho-SEK1ArrowR-HSA-451649 (Reactome)
R-HSA-168162 (Reactome) Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK.

JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183).

R-HSA-450222 (Reactome) Human p38 MAPK alpha forms a complex with MK2 even when the signaling pathway is not activated. This heterodimer is found mainly in the nucleus. The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined. The C-terminal regulatory domain of MK2 binds in the docking groove of p38 MAPK alpha, and the ATP-binding sites of both kinases are at the heterodimer interface (ter Haar et al. 2007).

Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334 (Ben-Levy et al. 1995).

The phosphorylation of MK2 at Thr-334 attenuates the affinity of the binary complex MK2:p38 alpha by an order of magnitude and leads to a large conformational change of an autoinhibitory domain in MK2. This conformational change unmasks not only the MK2 substrate-binding site but also the MK2 nuclear export signal (NES) thus leading to the MK2:p38 alpha translocation from the nucleus to the cytoplasm. Cytoplasmic active MK2 then phosphorylates downstream targets such as the heat-shock protein HSP27 and tristetraprolin (TTP) (Meng et al. 2002, Lukas et al. 2004, White et al. 2007).

MAPKAPK (MAPK-activated protein) kinase 3 (MK3, also known as 3pK) has been identified as the second p38 MAPK-activated kinase that is stimulated by different stresses (McLaughlin et al. 1996; Sithanandam et al. 1996; reviewed in Gaestel 2006). MK3 shows 75% sequence identity to MK2 and, like MK2, is activated by p38 MAPK alpha and p38 MAPK beta. MK3 phosphorylates peptide substrates with kinetic constants similar to MK2 and phosphorylates the same serine residues in HSP27 at the same relative rates as MK2 (Clifton et al. 1996) indicating an identical phosphorylation-site consensus sequence. Hence, it is assumed that its substrate spectrum is either identical to or at least overlapping with MK2.

R-HSA-450257 (Reactome) p38 MAPK alpha does not have a nuclear export signal (NES) and cannot leave the nucleus by itself, but rather needs to be associated with MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2). The NES of MAPKAPK2 facilitates the transport of both kinases from the nucleus to the cytoplasm but only after MK2 has been phosphorylated by p38alpha.

p38 MAPK alpha phosphorylates MK2 at Thr222, Ser272, and Thr334. The phosphorylation of Thr334 but not the kinase activity of MK2 has been demonstrated to be critical for the nuclear export of the p38 alpha - MK2 complex. Phosphorylation of Thr334 is believed to induce a conformational change in the complex exposing NES prior to interaction with the leptomycin B-sensitive nuclear export receptor.

R-HSA-450296 (Reactome) The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus.
R-HSA-450333 (Reactome) The MAPK level components of this cascade are p38MAPK-alpha, -beta, -gamma and -sigma. All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops.
R-HSA-450337 (Reactome) In human, phosphorylation of MKK4 and MKK7 by TAK1 occurs at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.

Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 and Ser257, Thr261 in MKK4.

Cell lines lacking MKK4 exhibit defective activation of JNK and AP-1 dependent transcription activity in response to some cellular stresses; JNK and p38 MAPK activities were decreased by around 80% and 20%, respectively, following deletion of the mkk4 gene.

R-HSA-450346 (Reactome) Human MKK3 and MKK6 are two closely related dual-specificity protein kinases. Both are activated by cellular stress and inflammatory cytokines, and both phosphorylate and activate p38 MAP kinase at its activation site Thr-Gly-Tyr but do not phosphorylate or activate Erk1/2 or SAPK/JNK.

Activation of MKK3 and MKK6 occurs through phosphorylation of serine and threonine residues at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loop. Residues involved into these protein kinases activation correspond to human sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6 .

R-HSA-450348 (Reactome) c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors.
R-HSA-451649 (Reactome) Tpl2 (also known as Cot) is constitutively bound to NFKB p105 (p105) which inhibits its MEK kinase activity in resting cells. Proteolysis of p105 frees Tpl2 from p105 and allows subsequent phosphorylation and activation of MEK1. Tpl2 can also activate SEK1. Phosphorylation of Tpl-2 is believed to play a role in its activation (Cho et al, 2005; Robinson et al. 2007).
Positions of phosphorylations represented here are inferred from general experimental data (Zheng & Guan, 1994).
p-MAP2K4/p-MAP2K7ArrowR-HSA-450337 (Reactome)
p-MAP2K4/p-MAP2K7mim-catalysisR-HSA-168162 (Reactome)
p-MAPK8/9/10ArrowR-HSA-168162 (Reactome)
p-MAPK8/9/10ArrowR-HSA-450348 (Reactome)
p-MAPK8/9/10R-HSA-450348 (Reactome)
p-MKK3/p-MKK6ArrowR-HSA-450296 (Reactome)
p-MKK3/p-MKK6ArrowR-HSA-450346 (Reactome)
p-MKK3/p-MKK6R-HSA-450296 (Reactome)
p-MKK3/p-MKK6mim-catalysisR-HSA-450333 (Reactome)
p-p38 MAPK:p-MAPKAPK2/3ArrowR-HSA-450222 (Reactome)
p-p38 MAPK:p-MAPKAPK2/3R-HSA-450257 (Reactome)
p38 MAPK:MAPKAPK2/3R-HSA-450333 (Reactome)
phospho-p38 MAPK :

phospho MAPKAPK2 or

phospho MaPKAPK3		ArrowR-HSA-450257 (Reactome)
phospho-p38 MAPK: MAPKAPK2/3ArrowR-HSA-450333 (Reactome)
phospho-p38 MAPK: MAPKAPK2/3R-HSA-450222 (Reactome)
phospho-p38 MAPK: MAPKAPK2/3mim-catalysisR-HSA-450222 (Reactome)

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