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.
| 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 |
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Download this section (compressed HTML)Q: 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?
Q: Beyond eEF2, does EEF2K have any other physiological substrates, or is eEF2 truly its sole target?
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.
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