DUSP6 (MKP-3, PYST1) is a cytoplasmic dual-specificity protein phosphatase of the MAP kinase phosphatase (MKP) family that selectively inactivates the extracellular signal-regulated kinases ERK1 and ERK2. An N-terminal rhodanese-like domain carrying a kinase-interaction motif docks ERK2, which both confers substrate specificity and allosterically activates the C-terminal catalytic domain (catalytic Cys293), allowing DUSP6 to remove the phosphates from the threonine and tyrosine of the ERK activation-loop TEY motif. DUSP6 has little activity toward JNK or p38. A CRM1-dependent nuclear export signal keeps DUSP6 predominantly cytoplasmic, and through ERK docking it also retains ERK in the cytoplasm. DUSP6 transcription is induced by FGF receptor/ERK signalling through Ets factors, while ERK phosphorylation of DUSP6 promotes its proteasomal turnover, so DUSP6 acts as an ERK-dependent negative-feedback regulator that sets the amplitude and duration of growth-factor-driven ERK signalling. Loss of mouse Dusp6 raises ERK activity and causes FGFR gain-of-function-like phenotypes (dwarfism, craniosynostosis, hearing loss), and human DUSP6 variants are associated with congenital hypogonadotropic hypogonadism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | TAS Reactome:R-HSA-5673001 | MODIFY | Summary: Reactome TAS placing DUSP6 in the RAF/MAP kinase cascade pathway. Reason: DUSP6 does not propagate the ERK/MAPK signal; it terminates it by dephosphorylating activated ERK1/2 as a feedback inhibitor [PMID:18321244; PMID:18771677]. Membership of the pathway is better expressed by the regulatory term GO:0070373 negative regulation of ERK1 and ERK2 cascade. Proposed replacements: negative regulation of ERK1 and ERK2 cascade Supporting Evidence: Reactome:R-HSA-203797 It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. PMID:18771677 MKP-3 acts in a negative feedback loop to suppress basal ERK1/2 when oncogenic Ras stimulates the Ras/Raf/MEK1/2/ERK1/2 cascade |
| GO:0004721 phosphoprotein phosphatase activity | IEA GO_REF:0000107 | MODIFY | Summary: IEA assignment of a generic protein phosphatase activity (phosphoprotein phosphatase activity) based on mapping or orthology. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 |
| GO:0004722 protein serine/threonine phosphatase activity | EXP PMID:8670865 Differential regulation of the MAP, SAP and RK/p38 kinases b... | MODIFY | Summary: Experimental support (Groom et al. 1996) for protein Ser/Thr phosphatase activity, derived from DUSP6 dephosphorylation of the ERK activation-loop phospho-threonine. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 |
| GO:0004722 protein serine/threonine phosphatase activity | IEA GO_REF:0000120 | MODIFY | Summary: IEA assignment of a generic protein phosphatase activity (protein serine/threonine phosphatase activity) based on mapping or orthology. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 |
| GO:0004725 protein tyrosine phosphatase activity | EXP PMID:8670865 Differential regulation of the MAP, SAP and RK/p38 kinases b... | MODIFY | Summary: Experimental support (Groom et al. 1996) for protein tyrosine phosphatase activity, derived from DUSP6 dephosphorylation of the ERK activation-loop phospho-tyrosine. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 |
| GO:0004725 protein tyrosine phosphatase activity | IEA GO_REF:0000120 | MODIFY | Summary: IEA assignment of a generic protein phosphatase activity (protein tyrosine phosphatase activity) based on mapping or orthology. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 |
| GO:0004725 protein tyrosine phosphatase activity | TAS Reactome:R-HSA-203797 | MODIFY | Summary: Reactome TAS (Reactome:R-HSA-203797) for a generic protein phosphatase activity, from the DUSP-mediated ERK/MAPK dephosphorylation reaction. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: Reactome:R-HSA-5675376 Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9 PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. |
| GO:0005515 protein binding | IPI PMID:12840032 Constitutive induction of p-Erk1/2 accompanied by reduced ac... | MODIFY | Summary: IPI: DUSP6 binds ERK1 (MAPK3) (PMID:12840032). Reason: The interaction partner is ERK1 (MAPK3), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. The cited senescence study (abstract-only in cache) used MKP3 as an ERK1/2 phosphatase; the abstract supports MKP3 action on p-ERK1/2. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:12840032 p-Erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2A (PP1/2A) and MAPK phosphatase 3 (MKP3) PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:12840032 Constitutive induction of p-Erk1/2 accompanied by reduced ac... | MODIFY | Summary: IPI: DUSP6 binds ERK2 (MAPK1) (PMID:12840032). Reason: The interaction partner is ERK2 (MAPK1), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. The cited senescence study (abstract-only in cache) used MKP3 as an ERK1/2 phosphatase; the abstract supports MKP3 action on p-ERK1/2. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:12840032 p-Erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2A (PP1/2A) and MAPK phosphatase 3 (MKP3) PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:18060821 Structural insights into the enzymatic mechanism of the path... | MODIFY | Summary: IPI: DUSP6 binds ERK2 (MAPK1) (PMID:18060821). Reason: The interaction partner is ERK2 (MAPK1), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. The cached abstract concerns the bacterial phosphothreonine lyase SpvC and does not mention DUSP6; the full text (not cached) presumably used the MKP3 docking interaction as a comparator. Deferring to the curator on the interaction itself, which is well established independently. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:27880917 Phenotypic and Interaction Profiling of the Human Phosphatas... | MODIFY | Summary: IPI: DUSP6 binds ERK1 (MAPK3) (PMID:27880917). Reason: The interaction partner is ERK1 (MAPK3), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. This row comes from a proteome-scale interaction screen, which independently recovers the canonical DUSP6-ERK docking interaction. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:27880917 Phenotypic and Interaction Profiling of the Human Phosphatas... | MODIFY | Summary: IPI: DUSP6 binds ERK2 (MAPK1) (PMID:27880917). Reason: The interaction partner is ERK2 (MAPK1), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. This row comes from a proteome-scale interaction screen, which independently recovers the canonical DUSP6-ERK docking interaction. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: IPI: DUSP6 binds ERK1 (MAPK3) (PMID:31980649). Reason: The interaction partner is ERK1 (MAPK3), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. This row comes from a proteome-scale interaction screen, which independently recovers the canonical DUSP6-ERK docking interaction. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: IPI: DUSP6 binds ERK2 (MAPK1) (PMID:31980649). Reason: The interaction partner is ERK2 (MAPK1), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. This row comes from a proteome-scale interaction screen, which independently recovers the canonical DUSP6-ERK docking interaction. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI: DUSP6 interaction with TXK from a high-throughput interactome screen (PMID:32296183). Reason: Generic protein binding from a proteome-scale screen with TXK provides no functional information and no follow-up links the interaction to DUSP6 activity. Removal is because the annotation is uninformative, not because the interaction is shown to be false. Supporting Evidence: PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: IPI: DUSP6 binds ERK1 (MAPK3) (PMID:32707033). Reason: The interaction partner is ERK1 (MAPK3), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. This row comes from a proteome-scale interaction screen, which independently recovers the canonical DUSP6-ERK docking interaction. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:32721402 Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder... | MODIFY | Summary: IPI: DUSP6 binds ERK2 (MAPK1) (PMID:32721402). Reason: The interaction partner is ERK2 (MAPK1), the physiological substrate of DUSP6. ERK1/2 binding via the N-terminal kinase-interaction motif is functionally meaningful: it confers substrate specificity, allosterically activates the phosphatase, and anchors ERK in the cytoplasm [PMID:11239467; PMID:15269220]. Generic 'protein binding' is uninformative; replace with GO:0051019 mitogen-activated protein kinase binding. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:32721402 the disease-causing amino acid substitutions clustering at the DRS significantly affect MKP3 binding and MKP3-mediated MAPK1 dephosphorylation of the regulatory residues, Thr185 and Tyr187 PMID:8670865 Pyst1 is able to form a physical complex with endogenous MAP kinase in Cos-1 cells PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI: DUSP6 interaction with APP from a high-throughput interactome screen (PMID:32814053). Reason: Generic protein binding from a proteome-scale screen with APP provides no functional information and no follow-up links the interaction to DUSP6 activity. Removal is because the annotation is uninformative, not because the interaction is shown to be false. Supporting Evidence: PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI: DUSP6 interaction with PHB2 from a high-throughput interactome screen (PMID:32814053). Reason: Generic protein binding from a proteome-scale screen with PHB2 provides no functional information and no follow-up links the interaction to DUSP6 activity. Removal is because the annotation is uninformative, not because the interaction is shown to be false. Supporting Evidence: PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-203797 | MARK AS OVER ANNOTATED | Summary: Reactome TAS: nucleoplasm, from a reaction grouping several ERK-directed DUSPs (R-HSA-203797). Reason: DUSP6 can transit the nucleus (it shuttles; nuclear accumulation is seen only when CRM1 export is blocked), but at steady state it is excluded from the nucleus and acts on ERK in the cytoplasm [PMID:15269220]. The nucleoplasm location derives from a Reactome reaction that groups nuclear and cytoplasmic DUSPs, and overstates the nuclear role of DUSP6. Supporting Evidence: PMID:15269220 the cytoplasmic localization of MKP-3 is mediated by a chromosome region maintenance-1 (CRM1)-dependent nuclear export pathway PMID:15269220 indicating that MKP-3 shuttles between the nucleus and cytoplasm |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: cytoplasm. Reason: DUSP6 is predominantly cytoplasmic at steady state due to a CRM1-dependent N-terminal nuclear export signal, and acts on ERK1/2 in the cytoplasm [PMID:8670865; PMID:15269220]. Supporting Evidence: PMID:8670865 Pyst1 is localized in the cytoplasm of transfected Cos-1 cells PMID:15269220 the cytoplasmic localization of MKP-3 is mediated by a chromosome region maintenance-1 (CRM1)-dependent nuclear export pathway |
| GO:0005737 cytoplasm | IDA PMID:8670865 Differential regulation of the MAP, SAP and RK/p38 kinases b... | ACCEPT | Summary: IDA: cytoplasm. Reason: DUSP6 is predominantly cytoplasmic at steady state due to a CRM1-dependent N-terminal nuclear export signal, and acts on ERK1/2 in the cytoplasm [PMID:8670865; PMID:15269220]. Supporting Evidence: PMID:8670865 Pyst1 is localized in the cytoplasm of transfected Cos-1 cells PMID:15269220 the cytoplasmic localization of MKP-3 is mediated by a chromosome region maintenance-1 (CRM1)-dependent nuclear export pathway |
| GO:0005737 cytoplasm | IDA PMID:9788880 Isolation of the human genes encoding the pyst1 and Pyst2 ph... | ACCEPT | Summary: IDA: cytoplasmic localization (Dowd et al. 1998). Reason: The cached abstract emphasises Pyst2 (DUSP7) localization, but the paper characterises both human Pyst1 and Pyst2 genes and the full text is not cached; cytoplasmic localization of Pyst1/DUSP6 is independently well established [PMID:8670865; PMID:15269220], so deferring to the curator. Supporting Evidence: PMID:9788880 This reinforces the conclusion that Pyst1 and Pyst2 are members of a distinct and structurally homologous subfamily of dual-specificity (Thr/Tyr) MAP kinase phosphatases. PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA: cytoplasm. Reason: DUSP6 is predominantly cytoplasmic at steady state due to a CRM1-dependent N-terminal nuclear export signal, and acts on ERK1/2 in the cytoplasm [PMID:8670865; PMID:15269220]. Supporting Evidence: PMID:8670865 Pyst1 is localized in the cytoplasm of transfected Cos-1 cells PMID:15269220 the cytoplasmic localization of MKP-3 is mediated by a chromosome region maintenance-1 (CRM1)-dependent nuclear export pathway |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: cytosol (GO_REF:0000033). Reason: DUSP6 is a soluble cytoplasmic MKP and is described as a major ERK1/2 inactivator in the cytosol [PMID:15632084]; consistent with nuclear-export-driven cytoplasmic localization [PMID:15269220]. Supporting Evidence: PMID:15632084 ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA: cytosol (GO_REF:0000052). Reason: DUSP6 is a soluble cytoplasmic MKP and is described as a major ERK1/2 inactivator in the cytosol [PMID:15632084]; consistent with nuclear-export-driven cytoplasmic localization [PMID:15269220]. Supporting Evidence: PMID:15632084 ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol PMID:15269220 MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5675376 | ACCEPT | Summary: TAS: cytosol (Reactome:R-HSA-5675376). Reason: DUSP6 is a soluble cytoplasmic MKP and is described as a major ERK1/2 inactivator in the cytosol [PMID:15632084]; consistent with nuclear-export-driven cytoplasmic localization [PMID:15269220]. Supporting Evidence: Reactome:R-HSA-5675376 Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9 PMID:15632084 ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9652816 | ACCEPT | Summary: TAS: cytosol (Reactome:R-HSA-9652816). Reason: DUSP6 is a soluble cytoplasmic MKP and is described as a major ERK1/2 inactivator in the cytosol [PMID:15632084]; consistent with nuclear-export-driven cytoplasmic localization [PMID:15269220]. Supporting Evidence: Reactome:R-HSA-5675376 Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9 PMID:15632084 ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: IBA: signal transduction (deep DUSP family node). Reason: DUSP6 does not propagate the ERK/MAPK signal; it terminates it by dephosphorylating activated ERK1/2 as a feedback inhibitor [PMID:18321244; PMID:18771677]. Membership of the pathway is better expressed by the regulatory term GO:0070373 negative regulation of ERK1 and ERK2 cascade. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH ROLE CONFLATION Sources checked: PANTHER:PTN004128558 SUPPORTS TRANSFER Deep DUSP-family node asserting generic signal transduction. DUSP6 lies inside the clade and does act in signalling, so the transfer is not wrong, but it conflates terminating the ERK signal with transducing it; the specific regulatory term GO:0070373 is preferred. Proposed replacements: negative regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:18321244 ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling PMID:18771677 MKP-3 acts in a negative feedback loop to suppress basal ERK1/2 when oncogenic Ras stimulates the Ras/Raf/MEK1/2/ERK1/2 cascade |
| GO:0008138 protein tyrosine/serine/threonine phosphatase activity | IEA GO_REF:0000107 | MODIFY | Summary: IEA assignment of a generic protein phosphatase activity (protein tyrosine/serine/threonine phosphatase activity) based on mapping or orthology. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 |
| GO:0008138 protein tyrosine/serine/threonine phosphatase activity | TAS Reactome:R-HSA-5675376 | MODIFY | Summary: Reactome TAS (Reactome:R-HSA-5675376) for a generic protein phosphatase activity, from the DUSP-mediated ERK/MAPK dephosphorylation reaction. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: Reactome:R-HSA-5675376 Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9 PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. |
| GO:0008138 protein tyrosine/serine/threonine phosphatase activity | TAS Reactome:R-HSA-9652816 | MODIFY | Summary: Reactome TAS (Reactome:R-HSA-9652816) for a generic protein phosphatase activity, from the DUSP-mediated ERK/MAPK dephosphorylation reaction. Reason: DUSP6 is a dual-specificity (phospho-Thr/phospho-Tyr) MAP kinase phosphatase whose established physiological substrates are the ERK1/2 activation-loop TEY residues; it shows very low activity toward JNK/SAPK and p38 [PMID:8670865]. The generic protein phosphatase term is correct chemistry but loses the MAP kinase substrate class that defines this enzyme, so the more specific GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity is preferred. Proposed replacements: MAP kinase tyrosine/serine/threonine phosphatase activity Supporting Evidence: Reactome:R-HSA-5675376 Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9 PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. |
| GO:0008330 protein tyrosine/threonine phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: protein tyrosine/threonine phosphatase activity, reflecting dephosphorylation of the pThr-X-pTyr motif. Reason: Chemically accurate description of the DUSP6 reaction (pThr and pTyr of the ERK TEY motif) inherited at the PAINT node; DUSP6 is a member of the dual-specificity (Thr/Tyr) MKP subfamily [PMID:9788880]. Less informative about substrate class than GO:0017017 but not wrong. Supporting Evidence: PMID:9788880 This reinforces the conclusion that Pyst1 and Pyst2 are members of a distinct and structurally homologous subfamily of dual-specificity (Thr/Tyr) MAP kinase phosphatases. file:human/DUSP6/DUSP6-deep-research-falcon.md It hydrolyses phosphate from the phosphothreonine and phosphotyrosine of the ERK activation-loop |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | REMOVE | Summary: IEA transfer from rat Dusp6 of response to xenobiotic stimulus. Reason: Ortholog transfer of an expression-response annotation; changes in Dusp6 transcript levels after drug exposure do not indicate that DUSP6 performs any part of a xenobiotic response, and DUSP6 induction is a general readout of ERK pathway activity [PMID:18321244]. Electronic over-propagation; remove. Supporting Evidence: PMID:18321244 ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling |
| GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: DUSP6 dephosphorylates both the phospho-Thr and phospho-Tyr of the ERK1/2 activation loop, inactivating the kinase; this is the defining molecular function of DUSP6/MKP-3. Reason: Correct and appropriately specific core MF (IBA). Groom et al. showed recombinant Pyst1/DUSP6 dephosphorylates and inactivates ERK in vitro and in vivo, with strong selectivity for ERK over JNK and p38 [PMID:8670865]; ERK2 docking to the N-terminal kinase-interaction domain activates the catalytic domain [PMID:11239467]. The IBA places this activity at the MKP clade node, consistent with the target's own experimental data. Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. |
| GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity | IDA PMID:8670865 Differential regulation of the MAP, SAP and RK/p38 kinases b... | ACCEPT | Summary: DUSP6 dephosphorylates both the phospho-Thr and phospho-Tyr of the ERK1/2 activation loop, inactivating the kinase; this is the defining molecular function of DUSP6/MKP-3. Reason: Correct and appropriately specific core MF (IDA). Groom et al. showed recombinant Pyst1/DUSP6 dephosphorylates and inactivates ERK in vitro and in vivo, with strong selectivity for ERK over JNK and p38 [PMID:8670865]; ERK2 docking to the N-terminal kinase-interaction domain activates the catalytic domain [PMID:11239467]. The IBA places this activity at the MKP clade node, consistent with the target's own experimental data. Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. |
| GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: DUSP6 dephosphorylates both the phospho-Thr and phospho-Tyr of the ERK1/2 activation loop, inactivating the kinase; this is the defining molecular function of DUSP6/MKP-3. Reason: Correct and appropriately specific core MF (IEA). Groom et al. showed recombinant Pyst1/DUSP6 dephosphorylates and inactivates ERK in vitro and in vivo, with strong selectivity for ERK over JNK and p38 [PMID:8670865]; ERK2 docking to the N-terminal kinase-interaction domain activates the catalytic domain [PMID:11239467]. The IBA places this activity at the MKP clade node, consistent with the target's own experimental data. Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 PMID:11239467 MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. |
| GO:0030154 cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA transfer from rat Dusp6 of cell differentiation. Reason: DUSP6-mediated ERK attenuation affects differentiation in some contexts (UniProt cites promotion of keratinocyte differentiation, PMID:29043977, not cached), but this is a downstream, context-dependent effect of ERK feedback. Very broad; kept as non-core. Supporting Evidence: PMID:17164422 DUSP6 serves in vivo as a negative feedback regulator of FGFR signaling |
| GO:0033550 MAP kinase tyrosine phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: MAP kinase tyrosine phosphatase activity, inherited from the MKP clade. Reason: DUSP6 removes the activation-loop phospho-Tyr of ERK1/2 as one half of its dual-specificity reaction [PMID:8670865]. The term is correct, though only partial; GO:0017017 (tyrosine/serine/threonine) captures the full reaction. The PAINT node placement within the DUSP/MKP family is consistent with DUSP6's biochemistry. Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. file:human/DUSP6/DUSP6-deep-research-falcon.md It hydrolyses phosphate from the phosphothreonine and phosphotyrosine of the ERK activation-loop |
| GO:0035335 peptidyl-tyrosine dephosphorylation | IDA PMID:8670865 Differential regulation of the MAP, SAP and RK/p38 kinases b... | ACCEPT | Summary: IDA: DUSP6 dephosphorylates the activation-loop phospho-tyrosine of ERK (Groom et al. 1996). Reason: Accurate process description of DUSP6 catalysis on ERK pTyr [PMID:8670865]; it accompanies the core MF GO:0017017. Retained as a valid, if partial, process annotation (DUSP6 also removes pThr). Supporting Evidence: PMID:8670865 Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: positive regulation of apoptotic process (node seeded by DUSP6's own experimental annotation). Reason: The PAINT node is grounded in DUSP6's own IDA annotation (PMID:10846176); the target appearing in WITH/FROM is expected, not circular. The effect is an indirect, context-dependent consequence of ERK1/2 inactivation, so kept as non-core. Supporting Evidence: PMID:10846176 The cytosolic MAP kinase phosphatase MAP kinase phosphatase-3 (MKP-3) induces apoptosis of endothelial cells in response to tumor necrosis factor alpha (TNFalpha) via dephosphorylation of the MAP kinase ERK1/2, leading to Bcl-2 proteolysis |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:10846176 Nitric oxide down-regulates MKP-3 mRNA levels: involvement i... | KEEP AS NON CORE | Summary: IDA: MKP-3 promotes TNFalpha-induced endothelial apoptosis via ERK1/2 dephosphorylation and Bcl-2 degradation (Rossig et al. 2000). Reason: The pro-apoptotic effect is a context-specific downstream consequence of ERK1/2 inactivation in endothelial cells rather than a dedicated apoptotic function [PMID:10846176]. Retained as non-core. Supporting Evidence: PMID:10846176 The cytosolic MAP kinase phosphatase MAP kinase phosphatase-3 (MKP-3) induces apoptosis of endothelial cells in response to tumor necrosis factor alpha (TNFalpha) via dephosphorylation of the MAP kinase ERK1/2, leading to Bcl-2 proteolysis |
| GO:0043409 negative regulation of MAPK cascade | IDA PMID:8670865 Differential regulation of the MAP, SAP and RK/p38 kinases b... | MODIFY | Summary: IDA: negative regulation of MAPK cascade. Reason: Correct in direction, but DUSP6 is selective for ERK1/2 and does not inhibit stress-activated JNK or p38 signalling in cells [PMID:8670865]; the more specific GO:0070373 negative regulation of ERK1 and ERK2 cascade is preferred. Proposed replacements: negative regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 PMID:15632084 a member of the MKP family that is highly specific for extracellular signal-regulated kinase 1 and 2 (ERK1/2) inactivation |
| GO:0043409 negative regulation of MAPK cascade | IEA GO_REF:0000117 | MODIFY | Summary: IEA: negative regulation of MAPK cascade. Reason: Correct in direction, but DUSP6 is selective for ERK1/2 and does not inhibit stress-activated JNK or p38 signalling in cells [PMID:8670865]; the more specific GO:0070373 negative regulation of ERK1 and ERK2 cascade is preferred. Proposed replacements: negative regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:8670865 Pyst1 displays very low activity towards the stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that these kinases are not physiological substrates for Pyst1 PMID:15632084 a member of the MKP family that is highly specific for extracellular signal-regulated kinase 1 and 2 (ERK1/2) inactivation |
| GO:0051409 response to nitrosative stress | IEP PMID:10846176 Nitric oxide down-regulates MKP-3 mRNA levels: involvement i... | MARK AS OVER ANNOTATED | Summary: IEP: NO donor decreased MKP-3 mRNA stability and protein levels in endothelial cells (Rossig et al. 2000). Reason: This is an expression readout: NO (used as an endothelial survival factor, not a nitrosative stress) destabilised MKP-3 mRNA, and the same study found no NO effect on MKP-3 phosphatase activity [PMID:10846176]. DUSP6 is regulated by NO rather than doing any of the work of a nitrosative stress response; the annotation is not supported as a functional role. Supporting Evidence: PMID:10846176 the endothelial cell survival factor nitric oxide (NO) down-regulated MKP-3 by destabilization of MKP-3 mRNA |
| GO:0060420 regulation of heart growth | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: regulation of heart growth, seeded from mouse Dusp6 (MGI:1914853). Reason: Mouse Dusp6 loss elevates ERK signalling and causes developmental phenotypes [PMID:17164422]; restraint of cardiac growth is a tissue-level consequence of DUSP6-mediated ERK feedback in the heart. Plausibly conserved but not a core function; kept as non-core. Supporting Evidence: PMID:17164422 Targeted inactivation of Dusp6 increases levels of phosphorylated ERK PMID:17164422 DUSP6 serves in vivo as a negative feedback regulator of FGFR signaling |
| GO:0070371 ERK1 and ERK2 cascade | IEA GO_REF:0000117 | MODIFY | Summary: IEA: ERK1 and ERK2 cascade. Reason: DUSP6 does not propagate the ERK/MAPK signal; it terminates it by dephosphorylating activated ERK1/2 as a feedback inhibitor [PMID:18321244; PMID:18771677]. Membership of the pathway is better expressed by the regulatory term GO:0070373 negative regulation of ERK1 and ERK2 cascade. Proposed replacements: negative regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:18321244 ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling PMID:18771677 MKP-3 acts in a negative feedback loop to suppress basal ERK1/2 when oncogenic Ras stimulates the Ras/Raf/MEK1/2/ERK1/2 cascade |
| GO:0070371 ERK1 and ERK2 cascade | TAS Reactome:R-HSA-112409 | MODIFY | Summary: TAS: ERK1 and ERK2 cascade. Reason: DUSP6 does not propagate the ERK/MAPK signal; it terminates it by dephosphorylating activated ERK1/2 as a feedback inhibitor [PMID:18321244; PMID:18771677]. Membership of the pathway is better expressed by the regulatory term GO:0070373 negative regulation of ERK1 and ERK2 cascade. Proposed replacements: negative regulation of ERK1 and ERK2 cascade Supporting Evidence: Reactome:R-HSA-203797 It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. PMID:18771677 MKP-3 acts in a negative feedback loop to suppress basal ERK1/2 when oncogenic Ras stimulates the Ras/Raf/MEK1/2/ERK1/2 cascade |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: negative regulation of ERK1 and ERK2 cascade. Reason: Core process. DUSP6 is an ERK1/2-specific MKP whose transcription is induced by FGF/ERK signalling and which dephosphorylates ERK1/2 as a negative-feedback regulator [PMID:18321244; PMID:17164422; PMID:18771677]. The PAINT node and orthology transfers agree with the human experimental evidence. Supporting Evidence: PMID:18321244 ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling PMID:17164422 DUSP6 serves in vivo as a negative feedback regulator of FGFR signaling PMID:18771677 knockdown of MKP-3, via siRNA, increased ERK1/2 phosphorylation |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | ACCEPT | Summary: IEA: negative regulation of ERK1 and ERK2 cascade. Reason: Core process. DUSP6 is an ERK1/2-specific MKP whose transcription is induced by FGF/ERK signalling and which dephosphorylates ERK1/2 as a negative-feedback regulator [PMID:18321244; PMID:17164422; PMID:18771677]. The PAINT node and orthology transfers agree with the human experimental evidence. Supporting Evidence: PMID:18321244 ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling PMID:17164422 DUSP6 serves in vivo as a negative feedback regulator of FGFR signaling PMID:18771677 knockdown of MKP-3, via siRNA, increased ERK1/2 phosphorylation |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IMP PMID:18771677 Reciprocal regulation of extracellular signal regulated kina... | ACCEPT | Summary: siRNA knockdown of endogenous MKP-3/DUSP6 increased basal ERK1/2 phosphorylation and prolonged EGF-stimulated ERK1/2 phosphorylation in Ras-transformed human cells. Reason: Direct loss-of-function evidence that endogenous DUSP6 limits ERK1/2 activity by dephosphorylating it, in an ERK-dependent negative-feedback loop [PMID:18771677]. DUSP6 does the work of this regulation itself (it catalyses ERK inactivation), so this is a core process annotation; consistent with mouse Dusp6 knockout phenotypes [PMID:17164422]. Supporting Evidence: PMID:18771677 MKP-3 acts in a negative feedback loop to suppress basal ERK1/2 when oncogenic Ras stimulates the Ras/Raf/MEK1/2/ERK1/2 cascade PMID:18771677 knockdown of MKP-3, via siRNA, increased ERK1/2 phosphorylation PMID:17164422 Targeted inactivation of Dusp6 increases levels of phosphorylated ERK |
| GO:0070848 response to growth factor | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA transfer from rat Dusp6 of response to growth factor. Reason: DUSP6 is transcriptionally induced by FGF via ERK/Ets and then acts as a feedback inhibitor of growth-factor-stimulated ERK signalling [PMID:18321244; PMID:17164422], so it does participate in the cellular response. Broad; the specific core process is GO:0070373. Kept as non-core. Supporting Evidence: PMID:18321244 ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling PMID:17164422 Fibroblast growth factor receptors (FGFRs) are required for transcription of Dusp6, which encodes MKP3, an extracellular signal-regulated kinase (ERK)-specific MKP |
Loading supporting content…
Download this section (compressed HTML)Q: Is DUSP6 dephosphorylation of non-MAPK substrates such as HER2 (reported in pancreatic cancer models) physiologically relevant outside tumour contexts, and does it warrant a broader MF annotation?
Q: Should the low-but-measurable activity of DUSP6 toward JNK/p38 in vitro be captured as a NOT annotation for p38/JNK-directed phosphatase activity, given the absence of an MF term specific to those MAPK subfamilies?
Q: How do the hypogonadotropic hypogonadism-associated DUSP6 variants affect ERK docking, catalytic activity, or stability?
Experiment: Kinetic comparison of wild-type DUSP6 and HH19-associated variants against diphospho-ERK2, JNK and p38 with and without ERK2 docking-domain engagement, to quantify substrate selectivity and allosteric activation.
Experiment: Endogenous DUSP6 knockout in human cells with re-expression of NES and kinase-interaction-motif mutants to separate catalytic ERK inactivation from cytoplasmic ERK anchoring.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)