AKT-2 is one of two C. elegans orthologs of the AGC-family serine/threonine kinase Akt/PKB. It has an N-terminal pleckstrin homology (PH) domain that binds phosphatidylinositol-3,4,5-trisphosphate (PIP3), a central kinase domain and an AGC-kinase C-terminal region. In the DAF-2 insulin/IGF-1-like receptor pathway, PIP3 generated by the AGE-1 PI3K recruits AKT-2, which is activated by PDK-1 and acts in a complex with AKT-1 and SGK-1. These kinases directly phosphorylate the FOXO transcription factor DAF-16 (and SKN-1/Nrf), retaining them in the cytoplasm and antagonizing their transcriptional programs. AKT-2 acts largely redundantly with AKT-1: the akt-1; akt-2 double loss-of-function causes daf-16-dependent constitutive dauer arrest, while single mutants have mild phenotypes. Together with AKT-1 and SGK-1 it also promotes embryonic cell survival, and contributes to lifespan and pathogen-resistance regulation. AKT-2 is expressed in neurons, pharyngeal muscle, rectal gland cells and spermatheca.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based assignment of generic protein kinase activity to AKT-2, which has a canonical Ser/Thr kinase domain. Reason: Correct but general; the more specific protein serine/threonine kinase activity (GO:0004674) is supported by IDA and IBA annotations. Broad IEA terms are acceptable. Supporting Evidence: PMID:15068796 All three kinases of this complex are able to directly phosphorylate DAF-16/FKHRL1 |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for protein serine/threonine kinase activity across the AGC kinase clade (PTN000683254). AKT-2 is a canonical AGC kinase and directly phosphorylates DAF-16 and SKN-1 in vitro. Reason: Core molecular function; the phylogenetic inference is corroborated by direct kinase assays on C. elegans AKT-2. Supporting Evidence: PMID:15068796 All three kinases of this complex are able to directly phosphorylate DAF-16/FKHRL1 PMID:18358814 The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1 |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:15068796 C. elegans SGK-1 is the critical component in the Akt/PKB ki... | ACCEPT | Summary: Hertweck et al. 2004 showed AKT-2 (with AKT-1 and SGK-1) directly phosphorylates DAF-16. Reason: Direct in vitro kinase assay on the C. elegans protein; core function. Supporting Evidence: PMID:15068796 All three kinases of this complex are able to directly phosphorylate DAF-16/FKHRL1 |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:18358814 Direct inhibition of the longevity-promoting factor SKN-1 by... | ACCEPT | Summary: Tullet et al. 2008 showed AKT-1, AKT-2 and SGK-1 phosphorylate SKN-1. Reason: Direct kinase assay with a physiological substrate; core function. Supporting Evidence: PMID:18358814 The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1 |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (ARBA/InterPro/EC 2.7.11.1) for protein serine/threonine kinase activity. Reason: Consistent with experimental data and the kinase domain. Supporting Evidence: PMID:15068796 All three kinases of this complex are able to directly phosphorylate DAF-16/FKHRL1 |
| GO:0005515 protein binding | IPI PMID:15068796 C. elegans SGK-1 is the critical component in the Akt/PKB ki... | REMOVE | Summary: IPI interaction of AKT-2 with DAF-16 (Hertweck et al. 2004). Reason: Generic protein binding is uninformative. The interaction reflects a kinase-substrate relationship already captured by protein serine/threonine kinase activity; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:15068796 C. elegans SGK-1 is the critical component in the Akt/PKB ki... | REMOVE | Summary: IPI interaction of AKT-2 with AKT-1 (Hertweck et al. 2004), part of the AKT-1/AKT-2/SGK-1 complex. Reason: Generic protein binding is uninformative; complex membership is captured by the protein kinase complex annotation. |
| GO:0005515 protein binding | IPI PMID:15068796 C. elegans SGK-1 is the critical component in the Akt/PKB ki... | REMOVE | Summary: IPI interaction of AKT-2 with SGK-1 (Hertweck et al. 2004). Reason: Generic protein binding is uninformative; complex membership is captured by the protein kinase complex annotation. |
| GO:0005515 protein binding | IPI PMID:18358814 Direct inhibition of the longevity-promoting factor SKN-1 by... | REMOVE | Summary: IPI interaction of AKT-2 with DAF-16 (Tullet et al. 2008). Reason: Generic protein binding is uninformative; the kinase-substrate relationship is captured by the kinase activity annotation. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based ATP binding, consistent with a functional protein kinase domain. Reason: ATP binding is intrinsic to kinase catalysis; correct, though not informative on its own. |
| GO:0005547 phosphatidylinositol-3,4,5-trisphosphate binding | IDA PMID:25383666 Caspase-activated phosphoinositide binding by CNT-1 promotes... | ACCEPT | Summary: Chen et al. 2014 showed in vitro that AKT-2 (with AKT-1 and SGK-1) binds strongly to PIP3, and that caspase-cleaved CNT-1 competes for this binding. Reason: Direct lipid-binding assay on C. elegans AKT-2, consistent with its PH domain and its recruitment downstream of AGE-1 PI3K. Supporting Evidence: PMID:25383666 Likewise, both AKT-2 and SGK-1 bound strongly to PIP3 and this binding was blocked by GST-CNT-1a pre-treated with CED-3 |
| GO:0005547 phosphatidylinositol-3,4,5-trisphosphate binding | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-based IEA for PIP3 binding via the PH domain. Reason: Consistent with the experimental IDA (PMID:25383666). Supporting Evidence: PMID:25383666 Likewise, both AKT-2 and SGK-1 bound strongly to PIP3 |
| GO:0008286 insulin receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for insulin receptor signaling pathway from the Akt subfamily node (PTN001219338), with C. elegans akt-1/akt-2 among the donor genes. Reason: AKT-2 is a core transducer of DAF-2 insulin receptor-like signaling; the IBA is consistent with genetic data on AKT-2 itself. Supporting Evidence: PMID:9716402 AKT-1 and AKT-2 signaling are indispensable for insulin receptor-like signaling in C. elegans |
| GO:0008286 insulin receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA IEA for insulin receptor signaling pathway. Reason: Consistent with genetic evidence (PMID:9716402). Supporting Evidence: PMID:9716402 two C. elegans Akt/PKB homologs, akt-1 and akt-2, transduce insulin receptor-like signals that inhibit dauer arrest |
| GO:0008286 insulin receptor signaling pathway | IMP PMID:9716402 Caenorhabditis elegans Akt/PKB transduces insulin receptor-l... | ACCEPT | Summary: Paradis and Ruvkun 1998 showed akt-1 and akt-2 transduce DAF-2/AGE-1 signals to antagonize DAF-16. Reason: Foundational genetic evidence that AKT-2 is a kinase step within the DAF-2 pathway; core process. Supporting Evidence: PMID:9716402 AKT-1 and AKT-2 signaling are indispensable for insulin receptor-like signaling in C. elegans |
| GO:0008340 determination of adult lifespan | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA for determination of adult lifespan. Reason: AKT-2 contributes to lifespan regulation through DAF-16 and SKN-1, but acts redundantly with AKT-1 and lifespan is a downstream organismal outcome of its signaling role. Supporting Evidence: PMID:18782349 akt-1 and akt-2 appear to function together to regulate lifespan |
| GO:0008340 determination of adult lifespan | IMP PMID:10638522 Mechanisms of life span determination in Caenorhabditis eleg... | KEEP AS NON CORE | Summary: IMP assertion attributed to a 1999 review (Vanfleteren and Braeckman) listing akt-2 among insulin-like pathway genes that regulate longevity. Reason: The cited paper is a review rather than a primary IMP study, but the role of akt-1/akt-2 in lifespan is supported by later primary work. Kept as a non-core, downstream organismal phenotype. Supporting Evidence: PMID:10638522 An insulin-like signaling cascade consisting of proteins encoded by the genes daf-2, age-1, akt-1, akt-2, daf-16 and daf-18 regulates dauer diapause, reproduction, and longevity |
| GO:0008582 regulation of synaptic assembly at neuromuscular junction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA for regulation of synaptic assembly at the neuromuscular junction, propagated from the C. elegans experimental annotation. Reason: Reflects the reported contribution of muscle insulin/IGF signaling to FSN-1-dependent NMJ development; a context-specific downstream role. |
| GO:0008582 regulation of synaptic assembly at neuromuscular junction | IGI PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media... | KEEP AS NON CORE | Summary: Hung et al. 2013 found reduced insulin/IGF signaling in postsynaptic muscle partially rescues fsn-1 synapse defects (IGI with fsn-1). Reason: Genetic interaction supports involvement of the IIS kinase cascade in NMJ development; not a core function of AKT-2. Full text not cached, so deferred to the curator. Supporting Evidence: PMID:23665919 The aberrant synapse morphology and synaptic transmission in fsn-1 mutants are partially and specifically rescued by reducing insulin/IGF-signalling activity in postsynaptic muscles |
| GO:0010468 regulation of gene expression | IDA PMID:15068796 C. elegans SGK-1 is the critical component in the Akt/PKB ki... | KEEP AS NON CORE | Summary: IDA for regulation of gene expression from Hertweck et al. 2004, presumably reflecting effects on DAF-16 target reporters. Reason: AKT-2 regulates gene expression only indirectly by phosphorylating and inhibiting DAF-16. Term is vague but not wrong; kept as non-core. |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA for regulation of gene expression. Reason: Indirect, via inhibition of DAF-16/SKN-1; vague but acceptable. |
| GO:0035556 intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for intracellular signal transduction across the AGC kinase clade. Reason: AKT-2 is an intracellular signaling kinase relaying the PIP3 signal; correct general process. |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for negative regulation of apoptotic process from the Akt subfamily node. Reason: Consistent with C. elegans evidence that AKT-1, AKT-2 and SGK-1 together promote cell survival during embryogenesis (Chen et al. 2014), though AKT-2 alone has a minor effect. Supporting Evidence: PMID:25383666 indicating that the presence of at least two AKT and SGK kinases is important for cell survival |
| GO:0043536 positive regulation of blood vessel endothelial cell migration | IBA GO_REF:0000033 | REMOVE | Summary: IBA for positive regulation of blood vessel endothelial cell migration, from mammalian AKT1/AKT3. Reason: C. elegans has no vasculature or blood vessel endothelium; this vertebrate-specific process cannot apply to the nematode ortholog (taxon-inappropriate propagation). Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN001219338 · PTN001219338 SUPPORTS SOURCE BUT NOT TARGET The Akt subfamily node is appropriate for kinase activity and insulin signaling; endothelial cell migration reflects vertebrate vascular biology, absent from nematodes. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based IEA for protein serine kinase activity. Reason: Consistent with demonstrated phosphorylation of DAF-16 and SKN-1 at Akt consensus Ser/Thr sites. |
| GO:1902911 protein kinase complex | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA IEA for protein kinase complex. Reason: Consistent with the experimentally reported AKT-1/AKT-2/SGK-1 complex (Hertweck et al. 2004). Supporting Evidence: PMID:15068796 SGK-1 forms a protein complex with the AKT kinases |
| GO:1902911 protein kinase complex | IPI PMID:15068796 C. elegans SGK-1 is the critical component in the Akt/PKB ki... | ACCEPT | Summary: Hertweck et al. 2004 showed by co-immunoprecipitation that SGK-1 forms a complex with AKT-1 and AKT-2. Reason: Experimental support for an AKT-1/AKT-2/SGK-1 kinase complex; the full text is not cached, so accepted on the curator's reading. Supporting Evidence: PMID:15068796 SGK-1 forms a protein complex with the AKT kinases |
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Download this section (compressed HTML)Q: Which DAF-16 or SKN-1 sites, or other substrates, are preferentially phosphorylated by AKT-2 versus AKT-1, and does this explain AKT-2's antagonism of AKT-1 in gonadal basement membrane maintenance?
Experiment: Quantitative phosphoproteomics of akt-1 and akt-2 single mutants, and akt-2 kinase-dead knock-in animals, to define AKT-2-specific substrates in vivo.
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