MAP2K5

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic (IEA) annotation (from rat Map2k5 IMP, PMID:20551324) to negative regulation of transcription by RNA polymerase II. Reason: MEK5 is a cytoplasmic MAP2K with no direct role in transcription; gene repression seen after MEK5D expression is mediated by ERK5 and KLF4 and represents indirect, secondary transcriptome changes. The well-documented transcriptional output of the pathway is activation (MEF2, KLF2, KLF4), not repression. Supporting Evidence: PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. PMID:16341264 this flow-mediated increase in expression occurs via a MEK5/ERK5/MEF2 signaling pathway
GO:0000122 negative regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Sequence-similarity (ISS) annotation (from rat Map2k5 IMP, PMID:20551324) to negative regulation of transcription by RNA polymerase II. Reason: MEK5 is a cytoplasmic MAP2K with no direct role in transcription; gene repression seen after MEK5D expression is mediated by ERK5 and KLF4 and represents indirect, secondary transcriptome changes. The well-documented transcriptional output of the pathway is activation (MEF2, KLF2, KLF4), not repression. Supporting Evidence: PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. PMID:16341264 this flow-mediated increase in expression occurs via a MEK5/ERK5/MEF2 signaling pathway
GO:0000165 MAPK cascade	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation of MEK5 to MAPK cascade. Reason: MEK5 is the MAP2K tier of the MEKK2/3-MEK5-ERK5 three-kinase cascade. MAPK cascade is correct though general; the specific child term ERK5 cascade (GO:0070375) is also annotated and is the core process. The PAINT node places MAPK cascade participation at the root of the MAP2K family, which MEK5 clearly belongs to. Supporting Evidence: PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5) PMID:15601854 MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation PMID:9384584 a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo
GO:0000165 MAPK cascade	IEA GO_REF:0000107	ACCEPT	Summary: Electronic (IEA) annotation of MEK5 to MAPK cascade. Reason: MEK5 is the MAP2K tier of the MEKK2/3-MEK5-ERK5 three-kinase cascade. MAPK cascade is correct though general; the specific child term ERK5 cascade (GO:0070375) is also annotated and is the core process. Supporting Evidence: PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5) PMID:15601854 MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation PMID:9384584 a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo
GO:0000165 MAPK cascade	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity (ISS) annotation of MEK5 to MAPK cascade. Reason: MEK5 is the MAP2K tier of the MEKK2/3-MEK5-ERK5 three-kinase cascade. MAPK cascade is correct though general; the specific child term ERK5 cascade (GO:0070375) is also annotated and is the core process. Supporting Evidence: PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5) PMID:15601854 MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation PMID:9384584 a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo
GO:0000165 MAPK cascade	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	ACCEPT	Summary: Sequence-similarity (ISS) annotation of MEK5 to MAPK cascade. Reason: MEK5 is the MAP2K tier of the MEKK2/3-MEK5-ERK5 three-kinase cascade. MAPK cascade is correct though general; the specific child term ERK5 cascade (GO:0070375) is also annotated and is the core process. Supporting Evidence: PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5) PMID:15601854 MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation PMID:9384584 a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo
GO:0004672 protein kinase activity	IEA GO_REF:0000120	MODIFY	Summary: IEA (ARBA/InterPro) annotation of protein kinase activity. Reason: Correct but too general. MEK5 is a dual-specificity MAP kinase kinase whose established substrate is ERK5; MAP kinase kinase activity (GO:0004708) is the informative term, as in the MAP2K3/MAP2K6 reviews. Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:14583600 MEKs activate their downstream MAPK by phosphorylation of threonine and tyrosine in the T- X-Y motif. MEK5 is the upstream BMK1 kinase PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0004672 protein kinase activity	TAS PMID:7759517 Components of a new human protein kinase signal transduction...	MODIFY	Summary: Traceable author statement of protein kinase activity from the original human MEK5 cloning paper (PMID:7759517). Reason: Correct but too general. MEK5 is a dual-specificity MAP kinase kinase whose established substrate is ERK5; MAP kinase kinase activity (GO:0004708) is the informative term, as in the MAP2K3/MAP2K6 reviews. Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:14583600 MEKs activate their downstream MAPK by phosphorylation of threonine and tyrosine in the T- X-Y motif. MEK5 is the upstream BMK1 kinase PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5) PMID:7759517 MAPK/ERK kinase 5 (MEK5) and extracellular signal-regulated kinase 5 (ERK5)
GO:0004708 MAP kinase kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation of MAP kinase kinase activity. Reason: Core function. MEK5 is a dual-specificity MAP2K that phosphorylates the Thr and Tyr of the ERK5 TEY activation motif; it is the only known ERK5 activator. The IBA reflects a PAINT node for the whole MAP2K clade; MEK5 is a bona fide member with its own supporting evidence. Supporting Evidence: PMID:14583600 MEKs activate their downstream MAPK by phosphorylation of threonine and tyrosine in the T- X-Y motif. MEK5 is the upstream BMK1 kinase PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5) PMID:9384584 a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo file:human/MAP2K5/MAP2K5-deep-research-falcon.md ERK5 remains the only firmly established direct physiological substrate of MEK5
GO:0004708 MAP kinase kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (IEA) annotation of MAP kinase kinase activity. Reason: Core function. MEK5 is a dual-specificity MAP2K that phosphorylates the Thr and Tyr of the ERK5 TEY activation motif; it is the only known ERK5 activator. Supporting Evidence: PMID:14583600 MEKs activate their downstream MAPK by phosphorylation of threonine and tyrosine in the T- X-Y motif. MEK5 is the upstream BMK1 kinase PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5) PMID:9384584 a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo file:human/MAP2K5/MAP2K5-deep-research-falcon.md ERK5 remains the only firmly established direct physiological substrate of MEK5
GO:0004713 protein tyrosine kinase activity	IEA GO_REF:0000116	MODIFY	Summary: Rhea-mapped (RHEA:10596) annotation of protein tyrosine kinase activity from the EC 2.7.12.2 tyrosine reaction. Reason: MEK5 phosphorylates a tyrosine only as part of dual Thr/Tyr phosphorylation of the ERK5 TEY motif; it is not a general tyrosine kinase. MAP kinase kinase activity (GO:0004708) describes the reaction accurately, as in the MAP2K3 review. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + PMID:14583600 MEKs activate their downstream MAPK by phosphorylation of threonine and tyrosine in the T- X-Y motif. MEK5 is the upstream BMK1 kinase
GO:0005515 protein binding	IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp...	MODIFY	Summary: IPI for MEK5 binding MAP3K3 (MEKK3), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:14743216). Reason: Bare protein binding is uninformative. MAP3K3 (MEKK3) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q99759: MAP3K3; NbExp=5; IntAct=EBI-307294, EBI-307281; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote...	REMOVE	Summary: GRB2 SH3 domain binding to a MEK5-derived peptide in an SH3 peptide-array screen (PMID:17474147). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. The assay used peptide arrays rather than full-length MEK5. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; P62993: GRB2; NbExp=2; IntAct=EBI-307294, EBI-401755; PMID:17474147 employed peptide arrays to identify such binding events
GO:0005515 protein binding	IPI PMID:18588859 TGF-beta activates ERK5 in human renal epithelial cells.	REMOVE	Summary: Co-immunoprecipitation of MEK5 with MEF2C in human renal proximal tubule epithelial cells after TGF-beta treatment (PMID:18588859, abstract only). Reason: Bare protein binding is uninformative. MEF2C is a substrate of ERK5, not of MEK5, and the reported association was measured together with phospho-ERK5, so it most likely reflects co-precipitation within a MEK5-ERK5-MEF2C complex rather than a direct MEK5 function. No more specific MF is supported. Removal does not imply the association is false. Supporting Evidence: PMID:18588859 TGF-beta increased the association of MEK5 with phospho-ERK5 and MEF2C PMID:9384584 MEF2C, is a protein substrate of BMK1
GO:0005515 protein binding	IPI PMID:18588859 TGF-beta activates ERK5 in human renal epithelial cells.	MODIFY	Summary: IPI for MEK5 binding MAPK7/ERK5, its only established substrate (PMID:18588859). Reason: Bare protein binding is uninformative. ERK5 (MAPK7) is the dedicated substrate of MEK5; MEK5 docks ERK5 via its N-terminal PB1/acidic docking region and phosphorylates the ERK5 TEY motif. The interaction is reproduced in many independent studies (IntAct NbExp=8). Mitogen-activated protein kinase binding (GO:0051019) captures this substrate-docking interaction, consistent with the MAP2K3/MAP2K6 reviews. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:18588859 TGF-beta increased the association of MEK5 with phospho-ERK5 and MEF2C file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q13164: MAPK7; NbExp=8; IntAct=EBI-307294, EBI-1213983; file:human/MAP2K5/MAP2K5-uniprot.txt Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	REMOVE	Summary: IPI for MEK5 binding LNX2 (yeast two-hybrid, Stitch-seq) from a large-scale interaction study (PMID:21516116). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q8N448: LNX2; NbExp=3; IntAct=EBI-307294, EBI-2340947;
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MODIFY	Summary: IPI for MEK5 binding MAP3K2 (MEKK2), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:21988832). Reason: Bare protein binding is uninformative. MAP3K2 (MEKK2) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q9Y2U5: MAP3K2; NbExp=7; IntAct=EBI-307294, EBI-357393; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p...	MODIFY	Summary: IPI for MEK5 binding the chaperone HSP90AB1 (PMID:22939624); MEK5, like most protein kinases, is an HSP90/CDC37 client. Reason: Bare protein binding is uninformative. HSP90AB1 is the partner; the interaction reflects MEK5 being an HSP90 client kinase (reproduced in 4 experiments in IntAct). Hsp90 protein binding (GO:0051879) captures this, as in the BRAF review. This is a chaperone-client relationship, not part of MEK5's signalling function, so it is non-core. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; P08238: HSP90AB1; NbExp=4; IntAct=EBI-307294, EBI-352572; PMID:22939624 We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MODIFY	Summary: IPI for MEK5 binding MAP3K3 (MEKK3), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:25241761). Reason: Bare protein binding is uninformative. MAP3K3 (MEKK3) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q99759: MAP3K3; NbExp=5; IntAct=EBI-307294, EBI-307281; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MODIFY	Summary: IPI for MEK5 binding MAPK7/ERK5, its only established substrate (PMID:28514442). Reason: Bare protein binding is uninformative. ERK5 (MAPK7) is the dedicated substrate of MEK5; MEK5 docks ERK5 via its N-terminal PB1/acidic docking region and phosphorylates the ERK5 TEY motif. The interaction is reproduced in many independent studies (IntAct NbExp=8). Mitogen-activated protein kinase binding (GO:0051019) captures this substrate-docking interaction, consistent with the MAP2K3/MAP2K6 reviews. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q13164: MAPK7; NbExp=8; IntAct=EBI-307294, EBI-1213983; file:human/MAP2K5/MAP2K5-uniprot.txt Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MODIFY	Summary: IPI for MEK5 binding MAP3K2 (MEKK2), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:28514442). Reason: Bare protein binding is uninformative. MAP3K2 (MEKK2) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q9Y2U5: MAP3K2; NbExp=7; IntAct=EBI-307294, EBI-357393; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m...	REMOVE	Summary: IPI for MEK5 binding LNX2 (yeast two-hybrid) from a large-scale interaction study (PMID:29892012). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q8N448: LNX2; NbExp=3; IntAct=EBI-307294, EBI-2340947;
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	REMOVE	Summary: IPI for MEK5 binding LNX2 (yeast two-hybrid) from a large-scale interaction study (PMID:31515488). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q8N448: LNX2; NbExp=3; IntAct=EBI-307294, EBI-2340947;
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	MODIFY	Summary: IPI for MEK5 binding the chaperone HSP90AB1 (PMID:31980649); MEK5, like most protein kinases, is an HSP90/CDC37 client. Reason: Bare protein binding is uninformative. HSP90AB1 is the partner; the interaction reflects MEK5 being an HSP90 client kinase (reproduced in 4 experiments in IntAct). Hsp90 protein binding (GO:0051879) captures this, as in the BRAF review. This is a chaperone-client relationship, not part of MEK5's signalling function, so it is non-core. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; P08238: HSP90AB1; NbExp=4; IntAct=EBI-307294, EBI-352572; PMID:22939624 We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	REMOVE	Summary: IPI for MEK5 binding SQSTM1 (p62) in an AP-MS study of the EGFR network (PMID:31980649). Reason: Bare protein binding is uninformative. SQSTM1 is a PB1-domain protein and UniProt records (by similarity) a MEK5-SQSTM1-atypical PKC complex, but the functional consequence for MEK5 is not established, so no specific MF term is justified. Removal does not imply the interaction is false. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q13501: SQSTM1; NbExp=5; IntAct=EBI-307294, EBI-307104; file:human/MAP2K5/MAP2K5-uniprot.txt SQSTM1 and PRKCZ or PRKCI (By similarity)
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	MODIFY	Summary: IPI for MEK5 binding MAP3K2 (MEKK2), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:31980649). Reason: Bare protein binding is uninformative. MAP3K2 (MEKK2) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q9Y2U5: MAP3K2; NbExp=7; IntAct=EBI-307294, EBI-357393; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MODIFY	Summary: IPI for MEK5 binding MAPK7/ERK5, its only established substrate (PMID:32296183). Reason: Bare protein binding is uninformative. ERK5 (MAPK7) is the dedicated substrate of MEK5; MEK5 docks ERK5 via its N-terminal PB1/acidic docking region and phosphorylates the ERK5 TEY motif. The interaction is reproduced in many independent studies (IntAct NbExp=8). Mitogen-activated protein kinase binding (GO:0051019) captures this substrate-docking interaction, consistent with the MAP2K3/MAP2K6 reviews. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q13164: MAPK7; NbExp=8; IntAct=EBI-307294, EBI-1213983; file:human/MAP2K5/MAP2K5-uniprot.txt Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: IPI for MEK5 binding SQSTM1 (p62) in the HuRI binary interactome screen (PMID:32296183). Reason: Bare protein binding is uninformative. The MEK5-SQSTM1 PB1-mediated association is plausible, but its functional role for MEK5 is not established, so no specific MF term is justified. Removal does not imply the interaction is false. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q13501: SQSTM1; NbExp=5; IntAct=EBI-307294, EBI-307104;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: IPI for MEK5 binding ZNF620 (HuRI Y2H) from a large-scale interaction study (PMID:32296183). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q6ZNG0: ZNF620; NbExp=3; IntAct=EBI-307294, EBI-4395669;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: IPI for MEK5 binding GUCD1 isoform 2 (HuRI Y2H) from a large-scale interaction study (PMID:32296183). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q96NT3-2: GUCD1; NbExp=3; IntAct=EBI-307294, EBI-11978177;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: IPI for MEK5 binding PFDN5 (HuRI Y2H) from a large-scale interaction study (PMID:32296183). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q99471: PFDN5; NbExp=3; IntAct=EBI-307294, EBI-357275;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: IPI for MEK5 binding ZNF426 (HuRI Y2H) from a large-scale interaction study (PMID:32296183). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q9BUY5: ZNF426; NbExp=3; IntAct=EBI-307294, EBI-743265;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: IPI for MEK5 binding DUSP21 (HuRI Y2H) from a large-scale interaction study (PMID:32296183). Reason: Bare protein binding (GO:0005515) is uninformative. This interaction comes from a proteome-scale screen with no functional follow-up linking the partner to MEK5 activity, so no more specific molecular function term is justified. Removal does not imply the reported interaction is false; the generic term simply adds no functional information. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q9H596: DUSP21; NbExp=3; IntAct=EBI-307294, EBI-7357329;
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	MODIFY	Summary: IPI for MEK5 binding the chaperone HSP90AB1 (PMID:32707033); MEK5, like most protein kinases, is an HSP90/CDC37 client. Reason: Bare protein binding is uninformative. HSP90AB1 is the partner; the interaction reflects MEK5 being an HSP90 client kinase (reproduced in 4 experiments in IntAct). Hsp90 protein binding (GO:0051879) captures this, as in the BRAF review. This is a chaperone-client relationship, not part of MEK5's signalling function, so it is non-core. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; P08238: HSP90AB1; NbExp=4; IntAct=EBI-307294, EBI-352572; PMID:22939624 We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37.
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	MODIFY	Summary: IPI for MEK5 binding MAPK7/ERK5, its only established substrate (PMID:32707033). Reason: Bare protein binding is uninformative. ERK5 (MAPK7) is the dedicated substrate of MEK5; MEK5 docks ERK5 via its N-terminal PB1/acidic docking region and phosphorylates the ERK5 TEY motif. The interaction is reproduced in many independent studies (IntAct NbExp=8). Mitogen-activated protein kinase binding (GO:0051019) captures this substrate-docking interaction, consistent with the MAP2K3/MAP2K6 reviews. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q13164: MAPK7; NbExp=8; IntAct=EBI-307294, EBI-1213983; file:human/MAP2K5/MAP2K5-uniprot.txt Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	MODIFY	Summary: IPI for MEK5 binding MAP3K3 (MEKK3), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:32707033). Reason: Bare protein binding is uninformative. MAP3K3 (MEKK3) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q99759: MAP3K3; NbExp=5; IntAct=EBI-307294, EBI-307281; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	MODIFY	Summary: IPI for MEK5 binding MAP3K2 (MEKK2), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:32707033). Reason: Bare protein binding is uninformative. MAP3K2 (MEKK2) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q9Y2U5: MAP3K2; NbExp=7; IntAct=EBI-307294, EBI-357393; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: IPI for MEK5 binding MAPK7/ERK5, its only established substrate (PMID:33961781). Reason: Bare protein binding is uninformative. ERK5 (MAPK7) is the dedicated substrate of MEK5; MEK5 docks ERK5 via its N-terminal PB1/acidic docking region and phosphorylates the ERK5 TEY motif. The interaction is reproduced in many independent studies (IntAct NbExp=8). Mitogen-activated protein kinase binding (GO:0051019) captures this substrate-docking interaction, consistent with the MAP2K3/MAP2K6 reviews. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q13164: MAPK7; NbExp=8; IntAct=EBI-307294, EBI-1213983; file:human/MAP2K5/MAP2K5-uniprot.txt Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: IPI for MEK5 binding MAP3K3 (MEKK3), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:33961781). Reason: Bare protein binding is uninformative. MAP3K3 (MEKK3) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q99759: MAP3K3; NbExp=5; IntAct=EBI-307294, EBI-307281; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: IPI for MEK5 binding MAP3K2 (MEKK2), an upstream MAP3K that activates MEK5 through PB1-PB1 heterodimerisation (PMID:33961781). Reason: Bare protein binding is uninformative. MAP3K2 (MEKK2) binds the MEK5 PB1 domain and phosphorylates/activates MEK5; this PB1-mediated association is required for ERK5 pathway activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, consistent with the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q9Y2U5: MAP3K2; NbExp=7; IntAct=EBI-307294, EBI-357393; PMID:12912994 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0005515 protein binding	IPI PMID:7759517 Components of a new human protein kinase signal transduction...	MODIFY	Summary: IPI for MEK5 binding MAPK7/ERK5, its only established substrate (PMID:7759517). Reason: Bare protein binding is uninformative. ERK5 (MAPK7) is the dedicated substrate of MEK5; MEK5 docks ERK5 via its N-terminal PB1/acidic docking region and phosphorylates the ERK5 TEY motif. The interaction is reproduced in many independent studies (IntAct NbExp=8). Mitogen-activated protein kinase binding (GO:0051019) captures this substrate-docking interaction, consistent with the MAP2K3/MAP2K6 reviews. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:7759517 ERK5 was identified by a specific interaction with the MEK5 mutants S311A/T315A and K195M in the yeast two-hybrid system. file:human/MAP2K5/MAP2K5-uniprot.txt Q13163; Q13164: MAPK7; NbExp=8; IntAct=EBI-307294, EBI-1213983; file:human/MAP2K5/MAP2K5-uniprot.txt Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation of ATP binding from kinase-domain InterPro signatures. Reason: MEK5 has a canonical protein kinase domain and uses ATP as phosphate donor; ATP binding is correct. Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Belongs to the protein kinase superfamily. STE Ser/Thr
GO:0005819 spindle	IEA GO_REF:0000107	UNDECIDED	Summary: Ensembl Compara transfer of spindle localization from mouse Map2k5 (mouse IDA, PMID:15509711). Reason: The mouse source (PMID:15509711) is a phospho-antibody immunocytochemistry survey of many kinases and transcription factors during M phase in trophoblast stem cells, a placental cell line and embryos, in which most phosphoproteins appeared to associate with the spindle complex. The cached record is abstract-only and does not name MEK5, and the full text is not openly available, so the MEK5-specific observation the mouse curator used cannot be checked here. No other study places MEK5 on the spindle or implicates it in mitosis; its characterised signalling occurs in a cytoplasmic MEKK2/3-MEK5-ERK5 complex. Left undecided rather than removed; at most this is a non-core, phospho-epitope-based observation. Supporting Evidence: PMID:15509711 Most phosphoproteins appeared to associate with the spindle complex during M phase PMID:7499418 MEK5 beta is ubiquitously distributed and primarily cytosolic
GO:0007165 signal transduction	IEA GO_REF:0000117	MODIFY	Summary: Electronic (IEA) annotation of MEK5 to signal transduction. Reason: Correct but too general. MEK5 functions specifically in the MEKK2/3-MEK5-ERK5 MAP kinase cascade, so ERK5 cascade (GO:0070375) is the appropriate specific process, as done for signal transduction in the MAP2K3/MAP2K6 reviews. Proposed replacements: ERK5 cascade Supporting Evidence: PMID:7759517 We have identified two components of a new protein kinase signaling cascade PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0007165 signal transduction	TAS PMID:7759517 Components of a new human protein kinase signal transduction...	MODIFY	Summary: Traceable author statement (TAS) annotation of MEK5 to signal transduction. Reason: Correct but too general. MEK5 functions specifically in the MEKK2/3-MEK5-ERK5 MAP kinase cascade, so ERK5 cascade (GO:0070375) is the appropriate specific process, as done for signal transduction in the MAP2K3/MAP2K6 reviews. Proposed replacements: ERK5 cascade Supporting Evidence: PMID:7759517 We have identified two components of a new protein kinase signaling cascade PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5)
GO:0030307 positive regulation of cell growth	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat Map2k5 (IMP, PMID:15623435): dominant-negative MEK5 blocked cardiotrophin-1-induced cardiomyocyte hypertrophy. Reason: Cardiomyocyte hypertrophic growth downstream of gp130/CT-1 requires MEK5-ERK5 signalling. This is a context-specific physiological output of the ERK5 cascade rather than a core function of MEK5. Supporting Evidence: PMID:15623435 CT-1-induced cell hypertrophy was suppressed by overexpression of a dominant-negative MEK5 mutant
GO:0032717 negative regulation of interleukin-8 production	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of interleukin-8 production, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This single-readout effect is several steps downstream of MEK5 (MEK5 -> ERK5 -> KLF4 -> target gene expression) and was observed with a constitutively active overexpressed mutant; it is an indirect consequence rather than a function of MEK5. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0032717 negative regulation of interleukin-8 production	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	MARK AS OVER ANNOTATED	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of interleukin-8 production, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This single-readout effect is several steps downstream of MEK5 (MEK5 -> ERK5 -> KLF4 -> target gene expression) and was observed with a constitutively active overexpressed mutant; it is an indirect consequence rather than a function of MEK5. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0034115 negative regulation of heterotypic cell-cell adhesion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of heterotypic cell-cell adhesion (leukocyte-endothelial adhesion), ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0034115 negative regulation of heterotypic cell-cell adhesion	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of heterotypic cell-cell adhesion (leukocyte-endothelial adhesion), ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0034392 negative regulation of smooth muscle cell apoptotic process	IEA GO_REF:0000107	MODIFY	Summary: Electronic (IEA) annotation from rat Map2k5 (IMP, PMID:20724525) to negative regulation of smooth muscle cell apoptotic process. Reason: The source study concerns cardiomyocytes: an ERK5-CHIP module downstream of IGF-1 destabilises ICER and inhibits cardiomyocyte apoptosis, attenuated in cardiac-specific constitutively active MEK5alpha transgenic mice. UniProt likewise describes MEK5 as a negative regulator of apoptosis in cardiomyocytes. Negative regulation of cardiac muscle cell apoptotic process (GO:0010667) better reflects the evidence; the role is indirect (via ERK5) and non-core. The cached record is abstract-only, but the open full text (PMC2992371) was checked during review: all MEK5 experiments use neonatal rat cardiomyocytes or cardiac-specific CA-MEK5alpha transgenic hearts, and smooth muscle cells are not studied, so the smooth muscle term in the rat source appears to be a term-selection slip. Proposed replacements: negative regulation of cardiac muscle cell apoptotic process Supporting Evidence: PMID:20724525 the ERK5-CHIP complex plays an obligatory role in inhibition of ICER expression, cardiomyocyte apoptosis, and cardiac dysfunction file:human/MAP2K5/MAP2K5-uniprot.txt negative regulator of apoptosis in cardiomyocytes via promotion of
GO:0034392 negative regulation of smooth muscle cell apoptotic process	ISS GO_REF:0000024	MODIFY	Summary: Sequence-similarity (ISS) annotation from rat Map2k5 (IMP, PMID:20724525) to negative regulation of smooth muscle cell apoptotic process. Reason: The source study concerns cardiomyocytes: an ERK5-CHIP module downstream of IGF-1 destabilises ICER and inhibits cardiomyocyte apoptosis, attenuated in cardiac-specific constitutively active MEK5alpha transgenic mice. UniProt likewise describes MEK5 as a negative regulator of apoptosis in cardiomyocytes. Negative regulation of cardiac muscle cell apoptotic process (GO:0010667) better reflects the evidence; the role is indirect (via ERK5) and non-core. The cached record is abstract-only, but the open full text (PMC2992371) was checked during review: all MEK5 experiments use neonatal rat cardiomyocytes or cardiac-specific CA-MEK5alpha transgenic hearts, and smooth muscle cells are not studied, so the smooth muscle term in the rat source appears to be a term-selection slip. Proposed replacements: negative regulation of cardiac muscle cell apoptotic process Supporting Evidence: PMID:20724525 the ERK5-CHIP complex plays an obligatory role in inhibition of ICER expression, cardiomyocyte apoptosis, and cardiac dysfunction file:human/MAP2K5/MAP2K5-uniprot.txt negative regulator of apoptosis in cardiomyocytes via promotion of
GO:0043124 negative regulation of canonical NF-kappaB signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of canonical NF-kappaB signal transduction, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0043124 negative regulation of canonical NF-kappaB signal transduction	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of canonical NF-kappaB signal transduction, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronic (IEA) annotation (from rat Map2k5 IMP, PMID:20551324) to positive regulation of transcription by RNA polymerase II. Reason: MEK5 activates ERK5, which phosphorylates and activates MEF2 transcription factors and induces KLF2/KLF4; MEK5 activation is both necessary and sufficient for flow-induced KLF2 transcription. MEK5 itself does not act on chromatin, so this indirect regulatory role is kept as non-core. Supporting Evidence: PMID:16341264 These results define a mechanism involving a MEK5/ERK5/MEF2 pathway linking flow and increases in KLF2 expression, whereby MEK5 activation is both required and sufficient for the flow-dependent upregulation of KLF2. PMID:15601854 MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation and for the regulation of the transcriptional activity of myocyte enhancer factor 2
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity (ISS) annotation (from rat Map2k5 IMP, PMID:20551324) to positive regulation of transcription by RNA polymerase II. Reason: MEK5 activates ERK5, which phosphorylates and activates MEF2 transcription factors and induces KLF2/KLF4; MEK5 activation is both necessary and sufficient for flow-induced KLF2 transcription. MEK5 itself does not act on chromatin, so this indirect regulatory role is kept as non-core. Supporting Evidence: PMID:16341264 These results define a mechanism involving a MEK5/ERK5/MEF2 pathway linking flow and increases in KLF2 expression, whereby MEK5 activation is both required and sufficient for the flow-dependent upregulation of KLF2. PMID:15601854 MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation and for the regulation of the transcriptional activity of myocyte enhancer factor 2
GO:0048009 insulin-like growth factor receptor signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from mouse Map2k5 (IDA, PMID:19654213): MEK5-ERK5 mediates IGF-2 pro-myogenic signalling in C2 myoblasts. Reason: In mouse myoblasts, IGF-2 signalling to ERK5 required MEK5 and constitutively active MEK5 rescued antisense Igf2 effects. MEK5 acts as a downstream relay in this context; the term is a valid but context-specific use of the ERK5 cascade. Supporting Evidence: PMID:19654213 transfection of myoblasts with dominant-negative MEK5 blocked the pro-myogenic action of IGF-2
GO:0050679 positive regulation of epithelial cell proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat Map2k5 (IDA, PMID:15631999): MEK5 knockdown reduced EGF-hyperresponsive proliferation of PCK rat biliary epithelial cells. Reason: MEK5-ERK5 signalling supports epithelial proliferation in this disease model; this is a context-specific output of the ERK5 cascade, not a core MEK5 function. Supporting Evidence: PMID:15631999 The increased proliferative activity was significantly inhibited by the transfection of short interfering RNA against MEK5 mRNA
GO:0051247 positive regulation of protein metabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Orthology-based (rat Map2k5) annotation to positive regulation of protein metabolic process, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. The term is vague and captures an indirect consequence of ERK5/KLF4-driven gene expression; it adds no informative description of MEK5 function. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0051247 positive regulation of protein metabolic process	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Orthology-based (rat Map2k5) annotation to positive regulation of protein metabolic process, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. The term is vague and captures an indirect consequence of ERK5/KLF4-driven gene expression; it adds no informative description of MEK5 function. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0060761 negative regulation of response to cytokine stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of response to cytokine stimulus, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0060761 negative regulation of response to cytokine stimulus	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of response to cytokine stimulus, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0070375 ERK5 cascade	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from rat Map2k5 (IMP, PMID:15631999) of ERK5 cascade. Reason: Core process. MEK5 is the dedicated and non-redundant MAP2K of the ERK5 cascade: it binds MEKK2/3 and ERK5 through its PB1 domain and N-terminal docking site and phosphorylates ERK5. Mek5-null mouse cells fail to activate ERK5. Supporting Evidence: PMID:23382384 MKK5 is the specific activator of extracellular regulated kinase 5 (ERK5) PMID:15601854 MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation PMID:16260599 The formation of the MEK5/extracellular signal-regulated kinase 5 (ERK5) complex is critical for MEK5 to activate ERK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5
GO:0071363 cellular response to growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to cellular response to growth factor stimulus, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. MEK5 is activated downstream of growth factors (e.g. EGF, serum) and relays these signals to ERK5; the term is correct but broad and describes context rather than MEK5's specific function. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. PMID:14583600 MEK5beta inhibited epidermal growth factor-induced BMK1 activation
GO:0071363 cellular response to growth factor stimulus	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to cellular response to growth factor stimulus, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. MEK5 is activated downstream of growth factors (e.g. EGF, serum) and relays these signals to ERK5; the term is correct but broad and describes context rather than MEK5's specific function. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. PMID:14583600 MEK5beta inhibited epidermal growth factor-induced BMK1 activation
GO:0071499 cellular response to laminar fluid shear stress	TAS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	ACCEPT	Summary: Traceable author statement (PMID:20551324) that the MEK5/Erk5 cascade mediates responses to laminar flow in endothelial cells. Reason: Laminar shear stress activates MEK5 which phosphorylates ERK5 and induces KLF2 via MEF2; dominant-negative MEK5 abolishes flow-induced ERK5 phosphorylation and KLF2 induction, and active MEK5 is sufficient. This mechanotransduction role is the best-characterised physiological context of MEK5 in the vasculature. Supporting Evidence: PMID:20551324 represents a candidate pathway mediating the beneficial effects of laminar flow PMID:16341264 this flow-mediated increase in expression occurs via a MEK5/ERK5/MEF2 signaling pathway PMID:16341264 These results define a mechanism involving a MEK5/ERK5/MEF2 pathway linking flow and increases in KLF2 expression, whereby MEK5 activation is both required and sufficient for the flow-dependent upregulation of KLF2.
GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of cell migration involved in sprouting angiogenesis, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of cell migration involved in sprouting angiogenesis, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	MODIFY	Summary: Rhea-mapped (RHEA:17989) annotation of protein serine kinase activity from the EC 2.7.12.2 serine reaction. Reason: The serine reaction listed under EC 2.7.12.2 is a generic part of the MAP2K EC class; MEK5's physiological substrate sites are Thr218/Tyr220 of ERK5. MAP kinase kinase activity (GO:0004708) is the accurate term, as in the MAP2K3 review. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:human/MAP2K5/MAP2K5-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + PMID:14583600 MEKs activate their downstream MAPK by phosphorylation of threonine and tyrosine in the T- X-Y motif. MEK5 is the upstream BMK1 kinase
GO:2000342 negative regulation of chemokine (C-X-C motif) ligand 2 production	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of chemokine (C-X-C motif) ligand 2 production, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This single-readout effect is several steps downstream of MEK5 (MEK5 -> ERK5 -> KLF4 -> target gene expression) and was observed with a constitutively active overexpressed mutant; it is an indirect consequence rather than a function of MEK5. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:2000342 negative regulation of chemokine (C-X-C motif) ligand 2 production	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	MARK AS OVER ANNOTATED	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of chemokine (C-X-C motif) ligand 2 production, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. This single-readout effect is several steps downstream of MEK5 (MEK5 -> ERK5 -> KLF4 -> target gene expression) and was observed with a constitutively active overexpressed mutant; it is an indirect consequence rather than a function of MEK5. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5.
GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of extrinsic apoptotic signaling pathway in absence of ligand, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. Endothelial survival is a well-documented output of MEK5-ERK5 signalling (also supported by the Mek5 knockout phenotype of increased apoptosis). This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. PMID:15601854 an essential regulator of cell survival that is required for normal embryonic development
GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	ISS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	KEEP AS NON CORE	Summary: Orthology-based (rat Map2k5) annotation to negative regulation of extrinsic apoptotic signaling pathway in absence of ligand, ultimately derived from MEK5D overexpression in human endothelial cells (PMID:20551324). Reason: The rat source annotation (RGD, Q62862) is an IMP from PMID:20551324, in which constitutively active MEK5 (MEK5D) was expressed in human primary endothelial cells; the effects were mediated by ERK5 and its transcriptional target KLF4. Endothelial survival is a well-documented output of MEK5-ERK5 signalling (also supported by the Mek5 knockout phenotype of increased apoptosis). This is a genuine downstream output of the MEK5-ERK5-KLF2/KLF4 endothelial program, but MEK5 acts several steps upstream as the kinase that activates ERK5, so the term is retained as non-core. Supporting Evidence: PMID:20551324 constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. PMID:15601854 an essential regulator of cell survival that is required for normal embryonic development

Gene Description

Existing Annotations Review

Core Functions

In endothelial cells MEK5 transduces laminar shear stress into ERK5 activation and MEF2-dependent induction of KLF2 (and KLF4), driving an atheroprotective, anti-inflammatory, pro-survival endothelial program.

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