Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0014069 postsynaptic density	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic transfer placing EEF2K at the postsynaptic density, consistent with its documented role in regulating local translation in neurons. Reason: A plausible neuronal site of action, but peripheral to EEF2K's core cytosolic eEF2-kinase function; retained as non-core. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0140245 regulation of translation at postsynapse	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: EEF2K regulates activity-dependent local translation at the postsynapse via eEF2 phosphorylation; a recognized neuronal role. Reason: A genuine specialized neuronal application of EEF2K's elongation-control function; non-core relative to its general molecular activity. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0004686 elongation factor-2 kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: The defining molecular function of EEF2K is phosphorylation of eEF2 to inhibit elongation. Supported by phylogenetic inference and abundant direct evidence. Reason: This is the core, specific molecular function of EEF2K (EC 2.7.11.20). Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro-based assignment of generic Ser/Thr kinase activity. EEF2K does phosphorylate a threonine residue, but it is an alpha-kinase structurally unrelated to the conventional Ser/Thr protein-kinase superfamily; the specific eEF2-kinase term is more accurate. Reason: Directionally correct (it is a Thr-directed kinase) but the generic term both under-specifies and slightly mischaracterizes the alpha-kinase; the core MF is elongation factor-2 kinase activity. Supporting Evidence: PMID:9144159 do not contain any sequence motifs characteristic of the eukaryotic protein kinase superfamily
GO:0004686 elongation factor-2 kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated assignment of the specific eEF2-kinase activity, redundant with and consistent with the experimental and IBA evidence. Reason: Agrees with direct experimental evidence; core molecular function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive
GO:0005509 calcium ion binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Automated assignment of calcium ion binding. EEF2K activity is calcium/calmodulin-dependent; calcium sensing is largely mediated through calmodulin binding rather than direct calcium binding by EEF2K. Reason: Plausible in the context of calcium/calmodulin regulation, but the salient, experimentally supported interaction is with calmodulin; retained as non-core. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Undergoes calcium/calmodulin-dependent intramolecular autophosphorylation
GO:0005516 calmodulin binding	IEA GO_REF:0000120	ACCEPT	Summary: Automated assignment of calmodulin binding, consistent with the strict requirement of calmodulin for EEF2K activity. Reason: Calmodulin binding is experimentally established and required for kinase activity; a core regulatory molecular function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Interacts with Calmodulin/CALM1; this interaction is strictly required for phosphorylation activity
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: ATP binding, the phosphate donor cofactor for the kinase reaction. Reason: ATP is the cosubstrate of the eEF2 kinase reaction (eEF2 + ATP gives eEF2-phosphate + ADP); ATP binding is a supported and necessary molecular function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Reaction=[translation elongation factor 2] + ATP = [translation elongation factor 2]-phosphate + ADP + H(+)
GO:0002931 response to ischemia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated phenotype/context association. EEF2K is activated under energy stress (via AMPK), so a role in ischemia is biologically plausible but indirect. Reason: Context association consistent with EEF2K's energy-stress activation; non-core relative to its molecular function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Upon activation by a variety of upstream kinases including AMPK or TRPM7
GO:0014069 postsynaptic density	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated assignment of postsynaptic density localization, redundant with the IBA postsynaptic-density annotation. Reason: Plausible neuronal site of action; non-core relative to the cytosolic eEF2-kinase function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0032869 cellular response to insulin stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated context association. Insulin/mTOR signaling inhibits EEF2K (via S6K/RSK), linking it to insulin responses. Reason: Consistent with EEF2K being a downstream target of insulin/mTOR signaling; non-core context annotation. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Phosphorylation by other kinases such as CDK1 and MAPK13 at Ser-359 or RPS6KA1 and RPS6KB1 at Ser-366 instead decrease EEF2K activity and promote protein synthesis
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated context association linking EEF2K activity to cell-survival/apoptosis outcomes, a downstream physiological consequence rather than a direct molecular action. Reason: Downstream phenotypic association (EEF2K modulates survival under stress); non-core relative to its kinase function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt In turn, the rate of protein synthesis is reduced.
GO:0043197 dendritic spine	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated assignment of dendritic spine localization, consistent with a neuronal role in local translation control. Reason: Plausible neuronal localization; non-core relative to the core cytosolic function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0045807 positive regulation of endocytosis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Automated context association of EEF2K with endocytosis regulation; a downstream/indirect link not reflecting its direct molecular activity. Reason: Indirect phenotypic association from automated transfer; not supported as a direct EEF2K function and uninformative for its core role. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0051965 positive regulation of synapse assembly	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated neuronal context association; a downstream developmental consequence of EEF2K-regulated translation rather than a direct function. Reason: Plausible neuronal/developmental association; non-core relative to the kinase function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0061003 positive regulation of dendritic spine morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated neuronal context association linking EEF2K-controlled translation to dendritic spine morphogenesis. Reason: Plausible neuronal developmental association; non-core relative to the molecular function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0071277 cellular response to calcium ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated context association consistent with EEF2K being a calcium/calmodulin-activated kinase that transduces calcium signals into translational control. Reason: Consistent with EEF2K's calcium/calmodulin dependence; non-core context annotation. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Undergoes calcium/calmodulin-dependent intramolecular autophosphorylation
GO:0071320 cellular response to cAMP	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated context association; cAMP/PKA signaling can modulate EEF2K activity. Reason: Plausible signaling-context association; non-core relative to the kinase function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Upon activation by a variety of upstream kinases including AMPK or TRPM7
GO:0071454 cellular response to anoxia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated context association. EEF2K is activated under energy/oxygen stress (AMPK), slowing elongation to conserve energy. Reason: Consistent with EEF2K's energy-stress activation; non-core context annotation. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Upon activation by a variety of upstream kinases including AMPK or TRPM7
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated assignment placing EEF2K at the glutamatergic synapse, consistent with its neuronal role in NMDA/mGluR-driven local translation control. Reason: Plausible neuronal site of action; non-core relative to the cytosolic kinase function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0140245 regulation of translation at postsynapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated assignment redundant with the IBA postsynaptic translation-regulation annotation. Reason: Genuine neuronal application of EEF2K's elongation-control function; non-core. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:1990416 cellular response to brain-derived neurotrophic factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Automated neuronal context association; BDNF signaling modulates eEF2 phosphorylation via EEF2K. Reason: Plausible neuronal signaling-context association; non-core relative to the kinase function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:1990637 response to prolactin	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Automated context association linking EEF2K to prolactin signaling; an indirect/peripheral link. Reason: Indirect phenotypic association from automated transfer; not supported as a direct EEF2K function and uninformative for its core role. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation.
GO:0004686 elongation factor-2 kinase activity	EXP PMID:11015200 Mapping the functional domains of elongation factor-2 kinase...	ACCEPT	Summary: Experimental demonstration (domain mapping, kinetics) of EEF2K phosphorylating eEF2, with measured KM and Vmax. Reason: Direct experimental support for the core eEF2-kinase activity. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt KM=1.2 uM for EEF2
GO:0046777 protein autophosphorylation	IDA PMID:23184662 Phosphorylation of eukaryotic elongation factor 2 (eEF2) by ...	KEEP AS NON CORE	Summary: EEF2K undergoes calcium/calmodulin-dependent intramolecular autophosphorylation. Note that PMID:23184662 chiefly concerns CDK2 phosphorylation of the substrate eEF2 (Ser595), and discusses EEF2K's own regulatory phosphorylations only in passing; the strongest autophosphorylation evidence comes from dedicated studies such as PMID:9144159. Reason: Autophosphorylation is a genuine EEF2K property (regulating its calcium/calmodulin dependence), but it is a regulatory feature rather than the core function, and the cited reference is not the primary autophosphorylation study. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Undergoes calcium/calmodulin-dependent intramolecular autophosphorylation
GO:0005829 cytosol	TAS Reactome:R-HSA-165758	ACCEPT	Summary: Reactome-curated cytosolic localization, the principal compartment where EEF2K phosphorylates eEF2. Reason: Cytosol is the core site of action for EEF2K's regulation of elongation. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive
GO:0004686 elongation factor-2 kinase activity	IDA PMID:9144159 Identification of a new class of protein kinases represented...	ACCEPT	Summary: Foundational direct evidence identifying and characterizing eEF-2 kinase activity as a new (alpha-kinase) class. Reason: Direct experimental support for the core eEF2-kinase activity. Supporting Evidence: PMID:9144159 eukaryotic elongation factor-2 kinase
GO:0005516 calmodulin binding	IDA PMID:9144159 Identification of a new class of protein kinases represented...	ACCEPT	Summary: Direct evidence that EEF2K is a calmodulin-binding kinase (the original calcium/calmodulin-dependent eEF2 kinase characterization). Reason: Calmodulin binding is directly demonstrated and required for activity; a core regulatory molecular function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Interacts with Calmodulin/CALM1; this interaction is strictly required for phosphorylation activity
GO:0046777 protein autophosphorylation	IDA PMID:9144159 Identification of a new class of protein kinases represented...	KEEP AS NON CORE	Summary: Direct evidence that EEF2K autophosphorylates, a regulatory property that modulates its calcium/calmodulin dependence. Reason: Autophosphorylation is a genuine regulatory feature of EEF2K but secondary to its core eEF2-kinase function. Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt Autophosphorylated at multiple residues, Thr-348 being the major site.
GO:0004672 protein kinase activity	TAS PMID:9144159 Identification of a new class of protein kinases represented...	KEEP AS NON CORE	Summary: General protein kinase activity, a parent of the specific eEF2-kinase activity. Reason: Correct but generic; the informative core MF is elongation factor-2 kinase activity. Supporting Evidence: PMID:9144159 eukaryotic elongation factor-2 kinase
GO:0005737 cytoplasm	TAS PMID:9144159 Identification of a new class of protein kinases represented...	ACCEPT	Summary: Cytoplasmic localization, consistent with the cytosolic site where EEF2K acts on eEF2. Reason: Correct compartment for EEF2K's core function (consistent with the Reactome cytosol annotation). Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive
GO:0006414 translational elongation	TAS PMID:9144159 Identification of a new class of protein kinases represented...	MODIFY	Summary: EEF2K is involved in the regulation of translational elongation. By phosphorylating and inactivating eEF2 it negatively regulates elongation; the more precise process is negative regulation of translational elongation. Reason: EEF2K does not itself carry out elongation; it negatively regulates it. A regulation term better captures the function than the bare process term. Proposed replacements: negative regulation of translational elongation Supporting Evidence: file:human/EEF2K/EEF2K-uniprot.txt renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced.
GO:0008135 translation factor activity, RNA binding	TAS PMID:9144159 Identification of a new class of protein kinases represented...	REMOVE	Summary: This annotation mischaracterizes EEF2K as a translation factor. EEF2K is a kinase; its substrate eEF2 is the translation elongation factor. EEF2K does not have translation-factor or RNA-binding activity. Reason: Incorrect molecular function. EEF2K is an alpha-kinase that phosphorylates eEF2, not a translation factor or RNA-binding protein; the term likely arose from conflation with its substrate. Supporting Evidence: PMID:9144159 eukaryotic elongation factor-2 kinase

Core Functions

Calcium/calmodulin-dependent alpha-kinase that phosphorylates the translation elongation factor eEF2 on Thr56, rendering eEF2 unable to bind the ribosome and thereby slowing peptide-chain elongation.

Molecular Function:

elongation factor-2 kinase activity

Cellular Locations:

cytosol

Supporting Evidence:

file:human/EEF2K/EEF2K-uniprot.txt
phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive
PMID:23184662
phosphorylation of eukaryotic elongation factor 2 (eEF2) on threonine 56 (T56) by eEF2 kinase (eEF2K)

By inactivating eEF2, EEF2K negatively regulates the rate of translational elongation, coupling protein synthesis to calcium, energy and stress signals (AMPK/TRPM7 activation; mTOR/S6K/RSK inhibition).

Molecular Function:

elongation factor-2 kinase activity

Cellular Locations:

cytosol

Supporting Evidence:

file:human/EEF2K/EEF2K-uniprot.txt
In turn, the rate of protein synthesis is reduced.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11015200

Mapping the functional domains of elongation factor-2 kinase.

EEF2K is an alpha-kinase that phosphorylates eEF2 (KM ~1.2 uM); calmodulin binding is strictly required for activity.

PMID:23184662

Phosphorylation of eukaryotic elongation factor 2 (eEF2) by cyclin A-cyclin-dependent kinase 2 regulates its inhibition by eEF2 kinase.

eEF2K phosphorylates eEF2 on Thr56, inactivating it; CDK2 phosphorylates eEF2 on Ser595, which regulates Thr56 phosphorylation by eEF2K during the cell cycle.

PMID:9144159

Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase.

eEF-2 kinase defines a new class of protein kinases (alpha-kinases) structurally unrelated to the conventional eukaryotic protein-kinase superfamily, homologous to myosin heavy chain kinase A.

Reactome:R-HSA-165758

Reactome pathway involving EEF2K (cytosolic localization)

Suggested Experiments

Experiment: Phosphoproteomics and in vitro kinase assays with purified EEF2K to test substrate specificity and confirm whether eEF2 is the only physiological substrate.

Experiment: Structure-function analysis of the alpha-kinase domain with calmodulin to define how calcium/calmodulin binding and autophosphorylation switch EEF2K between active and inactive states.

📚 Additional Documentation

Notes

(EEF2K-notes.md)

EEF2K (eukaryotic elongation factor 2 kinase) — research notes

UniProt O00418. Alpha-kinase (NOT classical eukaryotic protein-kinase superfamily fold); calcium/calmodulin-dependent.

Core function

PMID:9144159
UniProt FUNCTION: "Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation. Upon activation ... phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced."
Catalytic activity: eEF2 + ATP -> eEF2-phosphate + ADP; EC=2.7.11.20 [PMID:11015200, PMID:9144159]. Phosphorylates eEF2 on Thr56 PMID:23184662.
CaM strictly required PMID:11015200. Autophosphorylates (Thr348 major; Thr-348/Thr-56? autophos at multiple residues).

So core MF: elongation factor-2 kinase activity (GO:0004686). Core BP: negative regulation of translational elongation.

Annotation issues

GO:0004674 protein serine/threonine kinase activity (IEA) — EEF2K is an ALPHA-kinase, not a conventional Ser/Thr kinase; functionally it phosphorylates Thr but the term implies the classical fold. KEEP_AS_NON_CORE (it is a Ser/Thr-directed kinase) but core is the specific eEF2 kinase activity.
GO:0008135 translation factor activity, RNA binding (TAS 9144159) — WRONG: EEF2K is a kinase, not a translation factor / RNA-binding factor. Its substrate eEF2 is the translation factor. REMOVE/MARK_AS_OVER_ANNOTATED.
GO:0046777 protein autophosphorylation (IDA 23184662) — PMID:23184662 is actually about CDK2 phosphorylating eEF2 at S595; it does not primarily document EEF2K autophosphorylation. The 9144159 IDA autophosphorylation is the solid one. Flag 23184662 citation as possibly miscited for autophosphorylation; KEEP but note.
Synaptic / GO_REF:0000107 IEA terms (postsynaptic density, regulation of translation at postsynapse, dendritic spine, glutamatergic synapse, etc.) — EEF2K does have a documented role in synaptic/dendritic translation control; these are plausible but non-core (neuronal context). KEEP_AS_NON_CORE.
response to ischemia/anoxia/insulin/cAMP/calcium/BDNF/prolactin (GO_REF:0000107 IEA) — phenotype/context associations; KEEP_AS_NON_CORE or over-annotated. EEF2K is activated by energy stress (AMPK) so anoxia/ischemia context is plausible non-core.
GO:0004686 elongation factor-2 kinase activity (IBA, IEA, EXP 11015200, IDA 9144159) — ACCEPT core.
calmodulin binding (IEA, IDA 9144159) — ACCEPT (CaM-dependent kinase; required for activity).
calcium ion binding (IEA) — via CaM regulation; KEEP_AS_NON_CORE.
ATP binding (IEA) — kinase cofactor; ACCEPT/KEEP.

Pn Notes

(EEF2K-pn-notes.md)

EEF2K PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: O00418
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07c
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/EEF2K/EEF2K-ai-review.yaml
AIGR review HTML: present - genes/human/EEF2K/EEF2K-ai-review.html
Gene notes: present - genes/human/EEF2K/EEF2K-notes.md
GOA TSV: present - genes/human/EEF2K/EEF2K-goa.tsv
UniProt record: present - genes/human/EEF2K/EEF2K-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/EEF2K.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/EEF2K.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: EEF2K (eukaryotic elongation factor 2 kinase, also called calcium/calmodulin-dependent eEF2 kinase) is an atypical protein kinase of the alpha-kinase family, structurally unrelated to the classical eukaryotic protein-kinase superfamily and instead related to the myosin heavy chain kinases. Its single physiological substrate is the translation elongation factor eEF2, which it phosphorylates on Thr56; this phosphorylation prevents eEF2 from binding the ribosome, inactivating it and slowing the rate of peptide-chain elongation, thereby down-regulating global protein synthesis. EEF2K activity is strictly calcium/calmodulin-dependent and is further tuned by phosphorylation from multiple upstream signaling kinases (AMPK and TRPM7 activate it; mTOR/S6K, RSK and others inhibit it), coupling translation elongation to nutrient, energy and stress status. It acts in the cytosol and, in neurons, contributes to activity-dependent regulation of dendritic/synaptic translation.
Existing/core annotation action counts: ACCEPT: 9; KEEP_AS_NON_CORE: 20; MARK_AS_OVER_ANNOTATED: 2; MODIFY: 1; REMOVE: 1

PN Consistency Summary

Consistency: Internal review/notes are consistent and correct: EEF2K is a Ca2+/calmodulin-dependent alpha-kinase whose sole substrate is eEF2 (core MF GO:0004686 elongation factor-2 kinase activity). This DIRECTLY CONTRADICTS the PN node, which files EEF2K among "elongation factors" and projects GO:0003746 translation elongation factor activity. EEF2K is the regulatory kinase, not an EF. The review even REMOVES GO:0008135 (translation factor activity, RNA binding) as a substrate-conflation error — the same conflation the PN projection makes.
PN story / NEW pressure: Projected GO:0003746 is more_specific_than_existing_goa per dossier, but it is the wrong molecular function for this gene. EEF2K's function is already captured by GO:0004686 (in GOA, ACCEPTed core) and would be better served at the process level by GO:0045900 negative regulation of translational elongation (OLS-verified; already the review's MODIFY target for GO:0006414). The PN term over-reaches / is wrong.
Evidence alignment: Dossier gives no reference titles. Review anchors PMID:9144159 (alpha-kinase founding paper), PMID:11015200, PMID:23184662 — all VERIFIED and about kinase activity, none supporting EF activity. Divergence: PN node has no citation backing an EF role.
Verdict: Clear mis-mapping — EEF2K is the eEF2 kinase, not a translation elongation factor; GO:0003746 should not be projected. Recommended edits: [MAP] remove GO:0003746 projection for EEF2K; if a shared process is wanted use GO:0045900 negative regulation of translational elongation. Core MF GO:0004686 already in GOA.

Full Consistency Review

UniProt: O00418 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
PN placement: Translation|Cytosolic translation|Translation elongation|assorted elongation factors ; PN-node mapping: type assorted elongation factors → GO:0003746 translation elongation factor activity (mapped, ok_for_propagation); group Translation elongation → GO:0006414 context_only.
Consistency: Internal review/notes are consistent and correct: EEF2K is a Ca2+/calmodulin-dependent alpha-kinase whose sole substrate is eEF2 (core MF GO:0004686 elongation factor-2 kinase activity). This DIRECTLY CONTRADICTS the PN node, which files EEF2K among "elongation factors" and projects GO:0003746 translation elongation factor activity. EEF2K is the regulatory kinase, not an EF. The review even REMOVES GO:0008135 (translation factor activity, RNA binding) as a substrate-conflation error — the same conflation the PN projection makes.
PN story / NEW pressure: Projected GO:0003746 is more_specific_than_existing_goa per dossier, but it is the wrong molecular function for this gene. EEF2K's function is already captured by GO:0004686 (in GOA, ACCEPTed core) and would be better served at the process level by GO:0045900 negative regulation of translational elongation (OLS-verified; already the review's MODIFY target for GO:0006414). The PN term over-reaches / is wrong.
Mapping strategy: EEF2K argues the assorted elongation factors type conflates true EFs (eEF1A/eEF2) with elongation regulators. Projecting GO:0003746 onto a kinase is a category error; recommend excluding kinases/regulators from that type's MF projection.
Evidence alignment: Dossier gives no reference titles. Review anchors PMID:9144159 (alpha-kinase founding paper), PMID:11015200, PMID:23184662 — all VERIFIED and about kinase activity, none supporting EF activity. Divergence: PN node has no citation backing an EF role.
Verdict: Clear mis-mapping — EEF2K is the eEF2 kinase, not a translation elongation factor; GO:0003746 should not be projected. Recommended edits: [MAP] remove GO:0003746 projection for EEF2K; if a shared process is wanted use GO:0045900 negative regulation of translational elongation. Core MF GO:0004686 already in GOA.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07c
review_yaml: genes/human/EEF2K/EEF2K-ai-review.yaml
PN workbook rows: 1

PN row 1: Translation | Cytosolic translation | Translation elongation | assorted elongation factors

UniProt: O00418
In branches: TR
PN-node mapping records (path + ancestors):
- [type] Translation|Cytosolic translation|Translation elongation|assorted elongation factors
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0003746 translation elongation factor activity]
  rationale: This PN type groups cytosolic elongation factors. Translation elongation factor activity is the shared molecular-function target.
- [group] Translation|Cytosolic translation|Translation elongation
  status=context_only scope=too_broad_to_propagate GO=[GO:0006414 translational elongation]
  rationale: This PN group is an elongation-context bucket, but it also contains tRNA synthetases, tRNA deacylases, and multisynthetase-complex members whose direct shared assertions are narrower molecular functions or complexes. The elongation relationship is retained as context only.
- [class] Translation|Cytosolic translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
  rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
- [branch] Translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
  rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

Projected GO annotations (1)

GO:0003746 translation elongation factor activity | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Translation|Cytosolic translation|Translation elongation|assorted elongation factors

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: O00418
gene_symbol: EEF2K
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EEF2K (eukaryotic elongation factor 2 kinase, also called calcium/calmodulin-dependent
  eEF2 kinase) is an atypical protein kinase of the alpha-kinase family, structurally
  unrelated to the classical eukaryotic protein-kinase superfamily and instead related
  to the myosin heavy chain kinases. Its single physiological substrate is the translation
  elongation factor eEF2, which it phosphorylates on Thr56; this phosphorylation prevents
  eEF2 from binding the ribosome, inactivating it and slowing the rate of peptide-chain
  elongation, thereby down-regulating global protein synthesis. EEF2K activity is strictly
  calcium/calmodulin-dependent and is further tuned by phosphorylation from multiple
  upstream signaling kinases (AMPK and TRPM7 activate it; mTOR/S6K, RSK and others inhibit
  it), coupling translation elongation to nutrient, energy and stress status. It acts
  in the cytosol and, in neurons, contributes to activity-dependent regulation of dendritic/synaptic
  translation.
existing_annotations:
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic transfer placing EEF2K at the postsynaptic density, consistent
      with its documented role in regulating local translation in neurons.
    action: KEEP_AS_NON_CORE
    reason: A plausible neuronal site of action, but peripheral to EEF2K's core cytosolic
      eEF2-kinase function; retained as non-core.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0140245
    label: regulation of translation at postsynapse
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: EEF2K regulates activity-dependent local translation at the postsynapse
      via eEF2 phosphorylation; a recognized neuronal role.
    action: KEEP_AS_NON_CORE
    reason: A genuine specialized neuronal application of EEF2K's elongation-control
      function; non-core relative to its general molecular activity.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0004686
    label: elongation factor-2 kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: The defining molecular function of EEF2K is phosphorylation of eEF2 to
      inhibit elongation. Supported by phylogenetic inference and abundant direct evidence.
    action: ACCEPT
    reason: This is the core, specific molecular function of EEF2K (EC 2.7.11.20).
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: phosphorylates the elongation factor EEF2 at a single site,
        renders it unable to bind ribosomes and thus inactive
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based assignment of generic Ser/Thr kinase activity. EEF2K does
      phosphorylate a threonine residue, but it is an alpha-kinase structurally unrelated
      to the conventional Ser/Thr protein-kinase superfamily; the specific eEF2-kinase
      term is more accurate.
    action: KEEP_AS_NON_CORE
    reason: Directionally correct (it is a Thr-directed kinase) but the generic term
      both under-specifies and slightly mischaracterizes the alpha-kinase; the core
      MF is elongation factor-2 kinase activity.
    supported_by:
    - reference_id: PMID:9144159
      supporting_text: do not contain any sequence motifs characteristic of the eukaryotic
        protein kinase superfamily
- term:
    id: GO:0004686
    label: elongation factor-2 kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated assignment of the specific eEF2-kinase activity, redundant with
      and consistent with the experimental and IBA evidence.
    action: ACCEPT
    reason: Agrees with direct experimental evidence; core molecular function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: phosphorylates the elongation factor EEF2 at a single site,
        renders it unable to bind ribosomes and thus inactive
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Automated assignment of calcium ion binding. EEF2K activity is calcium/calmodulin-dependent;
      calcium sensing is largely mediated through calmodulin binding rather than direct
      calcium binding by EEF2K.
    action: KEEP_AS_NON_CORE
    reason: Plausible in the context of calcium/calmodulin regulation, but the salient,
      experimentally supported interaction is with calmodulin; retained as non-core.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Undergoes calcium/calmodulin-dependent intramolecular autophosphorylation
- term:
    id: GO:0005516
    label: calmodulin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated assignment of calmodulin binding, consistent with the strict
      requirement of calmodulin for EEF2K activity.
    action: ACCEPT
    reason: Calmodulin binding is experimentally established and required for kinase
      activity; a core regulatory molecular function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Interacts with Calmodulin/CALM1; this interaction is strictly
        required for phosphorylation activity
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP binding, the phosphate donor cofactor for the kinase reaction.
    action: ACCEPT
    reason: ATP is the cosubstrate of the eEF2 kinase reaction (eEF2 + ATP gives eEF2-phosphate
      + ADP); ATP binding is a supported and necessary molecular function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Reaction=[translation elongation factor 2] + ATP = [translation
        elongation factor 2]-phosphate + ADP + H(+)
- term:
    id: GO:0002931
    label: response to ischemia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated phenotype/context association. EEF2K is activated under energy
      stress (via AMPK), so a role in ischemia is biologically plausible but indirect.
    action: KEEP_AS_NON_CORE
    reason: Context association consistent with EEF2K's energy-stress activation; non-core
      relative to its molecular function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Upon activation by a variety of upstream kinases including AMPK
        or TRPM7
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Automated assignment of postsynaptic density localization, redundant with
      the IBA postsynaptic-density annotation.
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal site of action; non-core relative to the cytosolic eEF2-kinase
      function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0032869
    label: cellular response to insulin stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated context association. Insulin/mTOR signaling inhibits EEF2K (via
      S6K/RSK), linking it to insulin responses.
    action: KEEP_AS_NON_CORE
    reason: Consistent with EEF2K being a downstream target of insulin/mTOR signaling;
      non-core context annotation.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Phosphorylation by other kinases such as CDK1 and MAPK13 at
        Ser-359 or RPS6KA1 and RPS6KB1 at Ser-366 instead decrease EEF2K activity and
        promote protein synthesis
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated context association linking EEF2K activity to cell-survival/apoptosis
      outcomes, a downstream physiological consequence rather than a direct molecular
      action.
    action: KEEP_AS_NON_CORE
    reason: Downstream phenotypic association (EEF2K modulates survival under stress);
      non-core relative to its kinase function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: In turn, the rate of protein synthesis is reduced.
- term:
    id: GO:0043197
    label: dendritic spine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Automated assignment of dendritic spine localization, consistent with
      a neuronal role in local translation control.
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal localization; non-core relative to the core cytosolic
      function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0045807
    label: positive regulation of endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated context association of EEF2K with endocytosis regulation; a
      downstream/indirect link not reflecting its direct molecular activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Indirect phenotypic association from automated transfer; not supported
      as a direct EEF2K function and uninformative for its core role.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0051965
    label: positive regulation of synapse assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated neuronal context association; a downstream developmental consequence
      of EEF2K-regulated translation rather than a direct function.
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal/developmental association; non-core relative to the
      kinase function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0061003
    label: positive regulation of dendritic spine morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated neuronal context association linking EEF2K-controlled translation
      to dendritic spine morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal developmental association; non-core relative to the
      molecular function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0071277
    label: cellular response to calcium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated context association consistent with EEF2K being a calcium/calmodulin-activated
      kinase that transduces calcium signals into translational control.
    action: KEEP_AS_NON_CORE
    reason: Consistent with EEF2K's calcium/calmodulin dependence; non-core context
      annotation.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Undergoes calcium/calmodulin-dependent intramolecular autophosphorylation
- term:
    id: GO:0071320
    label: cellular response to cAMP
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated context association; cAMP/PKA signaling can modulate EEF2K activity.
    action: KEEP_AS_NON_CORE
    reason: Plausible signaling-context association; non-core relative to the kinase
      function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Upon activation by a variety of upstream kinases including AMPK
        or TRPM7
- term:
    id: GO:0071454
    label: cellular response to anoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated context association. EEF2K is activated under energy/oxygen
      stress (AMPK), slowing elongation to conserve energy.
    action: KEEP_AS_NON_CORE
    reason: Consistent with EEF2K's energy-stress activation; non-core context annotation.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Upon activation by a variety of upstream kinases including AMPK
        or TRPM7
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Automated assignment placing EEF2K at the glutamatergic synapse, consistent
      with its neuronal role in NMDA/mGluR-driven local translation control.
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal site of action; non-core relative to the cytosolic kinase
      function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0140245
    label: regulation of translation at postsynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated assignment redundant with the IBA postsynaptic translation-regulation
      annotation.
    action: KEEP_AS_NON_CORE
    reason: Genuine neuronal application of EEF2K's elongation-control function; non-core.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:1990416
    label: cellular response to brain-derived neurotrophic factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated neuronal context association; BDNF signaling modulates eEF2
      phosphorylation via EEF2K.
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal signaling-context association; non-core relative to
      the kinase function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:1990637
    label: response to prolactin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated context association linking EEF2K to prolactin signaling; an
      indirect/peripheral link.
    action: MARK_AS_OVER_ANNOTATED
    reason: Indirect phenotypic association from automated transfer; not supported
      as a direct EEF2K function and uninformative for its core role.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Threonine kinase that regulates protein synthesis by controlling
        the rate of peptide chain elongation.
- term:
    id: GO:0004686
    label: elongation factor-2 kinase activity
  evidence_type: EXP
  original_reference_id: PMID:11015200
  qualifier: enables
  review:
    summary: Experimental demonstration (domain mapping, kinetics) of EEF2K phosphorylating
      eEF2, with measured KM and Vmax.
    action: ACCEPT
    reason: Direct experimental support for the core eEF2-kinase activity.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: KM=1.2 uM for EEF2
- term:
    id: GO:0046777
    label: protein autophosphorylation
  evidence_type: IDA
  original_reference_id: PMID:23184662
  qualifier: involved_in
  review:
    summary: EEF2K undergoes calcium/calmodulin-dependent intramolecular autophosphorylation.
      Note that PMID:23184662 chiefly concerns CDK2 phosphorylation of the substrate
      eEF2 (Ser595), and discusses EEF2K's own regulatory phosphorylations only in
      passing; the strongest autophosphorylation evidence comes from dedicated studies
      such as PMID:9144159.
    action: KEEP_AS_NON_CORE
    reason: Autophosphorylation is a genuine EEF2K property (regulating its calcium/calmodulin
      dependence), but it is a regulatory feature rather than the core function, and
      the cited reference is not the primary autophosphorylation study.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Undergoes calcium/calmodulin-dependent intramolecular autophosphorylation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-165758
  qualifier: located_in
  review:
    summary: Reactome-curated cytosolic localization, the principal compartment where
      EEF2K phosphorylates eEF2.
    action: ACCEPT
    reason: Cytosol is the core site of action for EEF2K's regulation of elongation.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: phosphorylates the elongation factor EEF2 at a single site,
        renders it unable to bind ribosomes and thus inactive
- term:
    id: GO:0004686
    label: elongation factor-2 kinase activity
  evidence_type: IDA
  original_reference_id: PMID:9144159
  qualifier: enables
  review:
    summary: Foundational direct evidence identifying and characterizing eEF-2 kinase
      activity as a new (alpha-kinase) class.
    action: ACCEPT
    reason: Direct experimental support for the core eEF2-kinase activity.
    supported_by:
    - reference_id: PMID:9144159
      supporting_text: eukaryotic elongation factor-2 kinase
- term:
    id: GO:0005516
    label: calmodulin binding
  evidence_type: IDA
  original_reference_id: PMID:9144159
  qualifier: enables
  review:
    summary: Direct evidence that EEF2K is a calmodulin-binding kinase (the original
      calcium/calmodulin-dependent eEF2 kinase characterization).
    action: ACCEPT
    reason: Calmodulin binding is directly demonstrated and required for activity;
      a core regulatory molecular function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Interacts with Calmodulin/CALM1; this interaction is strictly
        required for phosphorylation activity
- term:
    id: GO:0046777
    label: protein autophosphorylation
  evidence_type: IDA
  original_reference_id: PMID:9144159
  qualifier: involved_in
  review:
    summary: Direct evidence that EEF2K autophosphorylates, a regulatory property that
      modulates its calcium/calmodulin dependence.
    action: KEEP_AS_NON_CORE
    reason: Autophosphorylation is a genuine regulatory feature of EEF2K but secondary
      to its core eEF2-kinase function.
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: Autophosphorylated at multiple residues, Thr-348 being the major
        site.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: TAS
  original_reference_id: PMID:9144159
  qualifier: enables
  review:
    summary: General protein kinase activity, a parent of the specific eEF2-kinase
      activity.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the informative core MF is elongation factor-2 kinase
      activity.
    supported_by:
    - reference_id: PMID:9144159
      supporting_text: eukaryotic elongation factor-2 kinase
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:9144159
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, consistent with the cytosolic site where EEF2K
      acts on eEF2.
    action: ACCEPT
    reason: Correct compartment for EEF2K's core function (consistent with the Reactome
      cytosol annotation).
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: phosphorylates the elongation factor EEF2 at a single site,
        renders it unable to bind ribosomes and thus inactive
- term:
    id: GO:0006414
    label: translational elongation
  evidence_type: TAS
  original_reference_id: PMID:9144159
  qualifier: involved_in
  review:
    summary: EEF2K is involved in the regulation of translational elongation. By phosphorylating
      and inactivating eEF2 it negatively regulates elongation; the more precise process
      is negative regulation of translational elongation.
    action: MODIFY
    reason: EEF2K does not itself carry out elongation; it negatively regulates it.
      A regulation term better captures the function than the bare process term.
    proposed_replacement_terms:
    - id: GO:0045900
      label: negative regulation of translational elongation
    supported_by:
    - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
      supporting_text: renders it unable to bind ribosomes and thus inactive. In turn,
        the rate of protein synthesis is reduced.
- term:
    id: GO:0008135
    label: translation factor activity, RNA binding
  evidence_type: TAS
  original_reference_id: PMID:9144159
  qualifier: enables
  review:
    summary: This annotation mischaracterizes EEF2K as a translation factor. EEF2K
      is a kinase; its substrate eEF2 is the translation elongation factor. EEF2K does
      not have translation-factor or RNA-binding activity.
    action: REMOVE
    reason: Incorrect molecular function. EEF2K is an alpha-kinase that phosphorylates
      eEF2, not a translation factor or RNA-binding protein; the term likely arose
      from conflation with its substrate.
    supported_by:
    - reference_id: PMID:9144159
      supporting_text: eukaryotic elongation factor-2 kinase
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11015200
  title: Mapping the functional domains of elongation factor-2 kinase.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_11015200.md) PubMed title
      matches the YAML title exactly; cached abstract reports EEF2K is an alpha-kinase
      that phosphorylates eEF2 and that calmodulin binding is strictly required for
      activity, supporting the core Ca2+/calmodulin-dependent eEF2-kinase molecular
      function. Full text not cached but abstract anchors the claim."
  findings:
  - statement: EEF2K is an alpha-kinase that phosphorylates eEF2 (KM ~1.2 uM); calmodulin
      binding is strictly required for activity.
    reference_section_type: ABSTRACT
- id: PMID:23184662
  title: Phosphorylation of eukaryotic elongation factor 2 (eEF2) by cyclin A-cyclin-dependent
    kinase 2 regulates its inhibition by eEF2 kinase.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_23184662.md) PubMed title
      matches the YAML title exactly; abstract states eEF2K phosphorylates eEF2 on
      Thr56 to inactivate it, directly supporting the core eEF2-kinase molecular
      function (cited in core_functions)."
  findings:
  - statement: eEF2K phosphorylates eEF2 on Thr56, inactivating it; CDK2 phosphorylates
      eEF2 on Ser595, which regulates Thr56 phosphorylation by eEF2K during the cell
      cycle.
    reference_section_type: ABSTRACT
- id: PMID:9144159
  title: Identification of a new class of protein kinases represented by eukaryotic
    elongation factor-2 kinase.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_9144159.md) PubMed title
      matches the YAML title exactly; abstract establishes eEF2 kinase as the
      founding member of the alpha-kinase class, structurally distinct from
      conventional protein kinases, supporting the core protein-kinase molecular
      function and its mechanistic classification."
  findings:
  - statement: eEF-2 kinase defines a new class of protein kinases (alpha-kinases)
      structurally unrelated to the conventional eukaryotic protein-kinase superfamily,
      homologous to myosin heavy chain kinase A.
    reference_section_type: ABSTRACT
- id: Reactome:R-HSA-165758
  title: Reactome pathway involving EEF2K (cytosolic localization)
  findings: []
core_functions:
- description: Calcium/calmodulin-dependent alpha-kinase that phosphorylates the translation
    elongation factor eEF2 on Thr56, rendering eEF2 unable to bind the ribosome and
    thereby slowing peptide-chain elongation.
  molecular_function:
    id: GO:0004686
    label: elongation factor-2 kinase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
    supporting_text: phosphorylates the elongation factor EEF2 at a single site, renders
      it unable to bind ribosomes and thus inactive
  - reference_id: PMID:23184662
    supporting_text: phosphorylation of eukaryotic elongation factor 2 (eEF2) on threonine
      56 (T56) by eEF2 kinase (eEF2K)
- description: By inactivating eEF2, EEF2K negatively regulates the rate of translational
    elongation, coupling protein synthesis to calcium, energy and stress signals (AMPK/TRPM7
    activation; mTOR/S6K/RSK inhibition).
  molecular_function:
    id: GO:0004686
    label: elongation factor-2 kinase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/EEF2K/EEF2K-uniprot.txt
    supporting_text: In turn, the rate of protein synthesis is reduced.
proposed_new_terms: []
suggested_questions:
- question: How is the balance of activating (AMPK, TRPM7) versus inhibitory (mTOR/S6K,
    RSK) phosphorylations on EEF2K integrated to set the elongation rate in different
    cellular states?
- question: Beyond eEF2, does EEF2K have any other physiological substrates, or is
    eEF2 truly its sole target?
suggested_experiments:
- description: Phosphoproteomics and in vitro kinase assays with purified EEF2K to
    test substrate specificity and confirm whether eEF2 is the only physiological substrate.
- description: Structure-function analysis of the alpha-kinase domain with calmodulin
    to define how calcium/calmodulin binding and autophosphorylation switch EEF2K between
    active and inactive states.

EEF2K

Gene Description