MAPK targets/ Nuclear events mediated by MAP kinases (Homo sapiens)
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Description
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. View original pathway at:Reactome.</div>
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | R-HSA-168053 (Reactome)  | ||
| ADP | Arrow | R-HSA-168136 (Reactome) | ||
| ADP | Arrow | R-HSA-198669 (Reactome) | ||
| ADP | Arrow | R-HSA-198731 (Reactome) | ||
| ADP | Arrow | R-HSA-198746 (Reactome) | ||
| ADP | Arrow | R-HSA-198756 (Reactome) | ||
| ADP | Arrow | R-HSA-199895 (Reactome) | ||
| ADP | Arrow | R-HSA-199910 (Reactome) | ||
| ADP | Arrow | R-HSA-199917 (Reactome) | ||
| ADP | Arrow | R-HSA-199929 (Reactome) | ||
| ADP | Arrow | R-HSA-199935 (Reactome) | ||
| ADP | Arrow | R-HSA-450325 (Reactome) | ||
| ATF1 | R-HSA-199910 (Reactome) | |||
| ATF2 | R-HSA-168053 (Reactome) | |||
| ATP | R-HSA-168053 (Reactome) | |||
| ATP | R-HSA-168136 (Reactome) | |||
| ATP | R-HSA-198669 (Reactome) | |||
| ATP | R-HSA-198731 (Reactome) | |||
| ATP | R-HSA-198746 (Reactome) | |||
| ATP | R-HSA-198756 (Reactome) | |||
| ATP | R-HSA-199895 (Reactome) | |||
| ATP | R-HSA-199910 (Reactome) | |||
| ATP | R-HSA-199917 (Reactome) | |||
| ATP | R-HSA-199929 (Reactome) | |||
| ATP | R-HSA-199935 (Reactome) | |||
| ATP | R-HSA-450325 (Reactome) | |||
| Activated MAPK
kinases ERK1/2, JNK, p38 | mim-catalysis | R-HSA-168053 (Reactome) | ||
| CREB1 | R-HSA-199895 (Reactome) | |||
| CREB1 | R-HSA-199917 (Reactome) | |||
| CREB1 | R-HSA-199935 (Reactome) | |||
| ELK1 | R-HSA-198731 (Reactome) | |||
| ERK-specific DUSP | mim-catalysis | R-HSA-203797 (Reactome) | ||
| ERK1/2/5 | Arrow | R-HSA-199959 (Reactome) | ||
| ERK1/2/5 | Arrow | R-HSA-203797 (Reactome) | ||
| FOS | R-HSA-450325 (Reactome) | |||
| H2O | R-HSA-199959 (Reactome) | |||
| H2O | R-HSA-203797 (Reactome) | |||
| JUN | R-HSA-168136 (Reactome) | |||
| MEF2 | R-HSA-199929 (Reactome) | |||
| PP2A-ABdeltaC complex | mim-catalysis | R-HSA-199959 (Reactome) | ||
| Phospho-MEF2 | Arrow | R-HSA-199929 (Reactome) | ||
| Phospho-Ribosomal protein S6 kinase | Arrow | R-HSA-198746 (Reactome) | ||
| Phospho-Ribosomal protein S6 kinase | mim-catalysis | R-HSA-199895 (Reactome) | ||
| Pi | Arrow | R-HSA-199959 (Reactome) | ||
| Pi | Arrow | R-HSA-203797 (Reactome) | ||
| R-HSA-168053 (Reactome) | the Raf–MEK–ERK pathway induces phosphorylation of ATF2 Thr71, whereas subsequent ATF2 Thr69 phosphorylation requires the Ral–RalGDS–Src–p38 pathway. Cooperation between ERK and p38 was found to be essential for ATF2 activation by these mitogens; the activity of p38 and JNK/SAPK in growth factor-stimulated fibroblasts is insufficient to phosphorylate ATF2 Thr71 or Thr69 + 71 significantly by themselves, while ERK cannot dual phosphorylate ATF2 Thr69 + 71 efficiently. | |||
| R-HSA-168136 (Reactome) | JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus. | |||
| R-HSA-168440 (Reactome) | At the beginning of this reaction, 1 molecule of 'c-Jun-P', and 1 molecule of 'ATF-2-P' are present. At the end of this reaction, 1 molecule of 'AP-1' is present. | |||
| R-HSA-198669 (Reactome) | MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by p38MAPK through phosphorylation at four key residues. | |||
| R-HSA-198731 (Reactome) | Following translocation to the nucleus, ERK1/2 directly phosphorylates key effectors, including the ubiquitous transcription factors ELK1 (Ets like protein 1). At least five residues in the C terminal domain of ELK1 are phosphorylated upon growth factor stimulation. ELK1 can form a ternary complex with the serum response factor (SRF) and consensus sequences, such as serum response elements (SRE), on DNA, thus stimulating transcription of a set of immediate early genes like c fos. | |||
| R-HSA-198746 (Reactome) | The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK. RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398. Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2. | |||
| R-HSA-198756 (Reactome) | MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues. | |||
| R-HSA-199895 (Reactome) | CREB is phosphorylated at Serine 133 by RSK1/2/3. | |||
| R-HSA-199910 (Reactome) | Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it. | |||
| R-HSA-199917 (Reactome) | p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3. | |||
| R-HSA-199929 (Reactome) | The MEF2 (Myocyte-specific enhancer factor 2) proteins constitute a family of transcription factors: MEF2A, MEF2B, MEF2C, and MEF2D. MEF2A and MEF2C are known substrates of ERK5, and their transactivating activity can be stimulated by ERK5 via direct phosphorylation. MEF2A and MEF2C are expressed in developing and adult brain including cortex and cerebellum. | |||
| R-HSA-199935 (Reactome) | MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB). | |||
| R-HSA-199959 (Reactome) | ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK. Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown. | |||
| R-HSA-203797 (Reactome) | Over 10 dual specificity phosphatases (DUSPs) active on MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity. | |||
| R-HSA-450292 (Reactome) | The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995). | |||
| R-HSA-450325 (Reactome) | The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity. On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325. Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover. | |||
| RPS6KA5 | R-HSA-198669 (Reactome) | |||
| RPS6KA5 | R-HSA-198756 (Reactome) | |||
| Ribosomal protein S6 kinase | R-HSA-198746 (Reactome) | |||
| p-2S-cJUN:p-2S,2T-cFOS | Arrow | R-HSA-450292 (Reactome) | ||
| p-2S-cJUN:p-2T-ATF2 | Arrow | R-HSA-168440 (Reactome) | ||
| p-4S,T336-ELK1 | Arrow | R-HSA-198731 (Reactome) | ||
| p-ERK1/2/5 | R-HSA-199959 (Reactome) | |||
| p-ERK1/2/5 | R-HSA-203797 (Reactome) | |||
| p-ERK1/2/5 | mim-catalysis | R-HSA-198746 (Reactome) | ||
| p-MAPK p38 alpha/beta | mim-catalysis | R-HSA-198669 (Reactome) | ||
| p-MAPK8/9/10 | mim-catalysis | R-HSA-168136 (Reactome) | ||
| p-S133-CREB1 | Arrow | R-HSA-199895 (Reactome) | ||
| p-S133-CREB1 | Arrow | R-HSA-199917 (Reactome) | ||
| p-S133-CREB1 | Arrow | R-HSA-199935 (Reactome) | ||
| p-S212,S360,S376,T581-RPS6KA5 | Arrow | R-HSA-198669 (Reactome) | ||
| p-S212,S360,S376,T581-RPS6KA5 | Arrow | R-HSA-198756 (Reactome) | ||
| p-S212,S360,S376,T581-RPS6KA5 | mim-catalysis | R-HSA-199910 (Reactome) | ||
| p-S212,S360,S376,T581-RPS6KA5 | mim-catalysis | R-HSA-199935 (Reactome) | ||
| p-S63,S73-JUN | Arrow | R-HSA-168136 (Reactome) | ||
| p-S63,S73-JUN | R-HSA-168440 (Reactome) | |||
| p-S63,S73-JUN | R-HSA-450292 (Reactome) | |||
| p-S63-ATF1 | Arrow | R-HSA-199910 (Reactome) | ||
| p-T,Y MAPK dimers | mim-catalysis | R-HSA-198731 (Reactome) | ||
| p-T,Y MAPK dimers | mim-catalysis | R-HSA-198756 (Reactome) | ||
| p-T,Y MAPK dimers | mim-catalysis | R-HSA-450325 (Reactome) | ||
| p-T218,Y220-MAPK7 | mim-catalysis | R-HSA-199929 (Reactome) | ||
| p-T222,S272-MAPKAPK2 | mim-catalysis | R-HSA-199917 (Reactome) | ||
| p-T325,T331,S362,S374-FOS | Arrow | R-HSA-450325 (Reactome) | ||
| p-T325,T331,S362,S374-FOS | R-HSA-450292 (Reactome) | |||
| p-T69,T71-ATF2 | Arrow | R-HSA-168053 (Reactome) | ||
| p-T69,T71-ATF2 | R-HSA-168440 (Reactome) |
