aak-2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004674 protein serine/threonine kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: AAK-2 is the catalytic alpha subunit of AMPK, a serine/threonine kinase that phosphorylates substrates on serine and threonine residues. The kinase domain is well-characterized and the protein has demonstrated kinase activity (PMID:15574588, PMID:29414769). Reason: This is a core molecular function annotation. AAK-2 contains a protein kinase domain (InterPro IPR000719) and demonstrates serine/threonine kinase activity. The IBA annotation is well-supported by phylogenetic inference from characterized AMPK alpha subunits. Supporting Evidence: PMID:15574588 The C. elegans AMP-activated protein kinase alpha subunit AAK-2 is activated by AMP file:worm/aak-2/aak-2-deep-research-falcon.md model: Edison Scientific Literature
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: AMPK alpha subunits are known to translocate to the nucleus in other systems. However, direct experimental evidence for nuclear localization of AAK-2 in C. elegans was not provided in the available literature. Reason: The IBA annotation is based on conserved localization patterns across AMPK alpha orthologs. AMPK is known to phosphorylate nuclear substrates. While the primary literature (PMID:18408008) shows cytoplasmic, axonal, and neuronal cell body localization, nuclear localization is consistent with AMPK function in regulating transcription factors.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Cytoplasmic localization of AAK-2 is well-supported by experimental evidence from PMID:18408008 showing AAK-2::GFP fusion protein in the cytoplasm. Reason: IBA annotation is supported by direct experimental evidence (IDA from PMID:18408008). The AAK-2::GFP fusion protein was observed in the cytoplasm in multiple cell types. Supporting Evidence: PMID:18408008 expression of the AAK-2::green fluorescent protein fusion protein was observed in the ventral cord, some neurons, body wall muscle, pharynx, vulva, somatic gonad, and excretory cell
GO:0010508 positive regulation of autophagy	IBA GO_REF:0000033	ACCEPT	Summary: AMPK is a well-established positive regulator of autophagy across eukaryotes, functioning by phosphorylating ULK1 and inhibiting mTORC1. This function is conserved based on phylogenetic inference from characterized AMPK orthologs. Reason: This represents a conserved core function of AMPK. The IBA annotation is supported by extensive literature on AMPK-autophagy connections in other systems and by C. elegans studies showing AAK-2's role in stress resistance and metabolic homeostasis.
GO:1904262 negative regulation of TORC1 signaling	IBA GO_REF:0000033	ACCEPT	Summary: AMPK negatively regulates mTORC1/TORC1 signaling, a core conserved function. This is supported by Reactome pathway R-CEL-380972 (Energy dependent regulation of mTOR by LKB1-AMPK). Reason: This is a core conserved function of AMPK alpha subunits. The IBA annotation is well-supported by phylogenetic inference from characterized AMPK orthologs that inhibit TORC1.
GO:1990044 protein localization to lipid droplet	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: AMPK has been implicated in lipid metabolism regulation in C. elegans (PMID:28128367). While the specific function of localizing proteins to lipid droplets is conserved in mammalian AMPK, direct evidence for this specific annotation in AAK-2 is limited. Reason: While AAK-2/AMPK clearly regulates lipid metabolism in C. elegans, the specific function of protein localization to lipid droplets is inferred from mammalian orthologs. This should be retained but considered as a secondary/inferred function rather than a demonstrated core function.
GO:0031588 nucleotide-activated protein kinase complex	IBA GO_REF:0000033	ACCEPT	Summary: AAK-2 is the catalytic alpha subunit of the AMPK heterotrimeric complex. UniProt indicates it forms a complex with regulatory subunits and interacts with AAKB-2 (beta subunit). Reason: This is a core annotation. AAK-2 functions as part of the AMPK heterotrimeric complex with beta (aakb-1, aakb-2) and gamma subunits. The complex is activated by nucleotides (AMP/ADP).
GO:0042149 cellular response to glucose starvation	IBA GO_REF:0000033	ACCEPT	Summary: AMPK is the master regulator of cellular responses to energy stress, including glucose starvation. AAK-2 links energy levels to lifespan (PMID:15574588) and responds to metabolic stress conditions. Reason: This is a core conserved function. AMPK activation by energy stress (reflected in AMP:ATP ratio changes) is central to its physiological role. The C. elegans literature supports AAK-2 function in metabolic stress responses. Supporting Evidence: PMID:15574588 The AMP:ATP ratio, a measure of energy levels, increases with age in Caenorhabditis elegans and can be used to predict life expectancy
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: AAK-2 binds ATP for its kinase activity. This is a general annotation inferred from the kinase function and domain architecture. Reason: Correct but general annotation. AAK-2 contains ATP-binding domains (InterPro IPR000719, IPR017441) and requires ATP binding for catalytic activity.
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: AAK-2 is a protein kinase as annotated from InterPro domains. This is a parent term of the more specific annotations. Reason: Correct but redundant with the more specific GO:0004674 (protein serine/threonine kinase activity) and GO:0004679 (AMPK activity). Retained as a general IEA annotation.
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate annotation of the IBA annotation. AAK-2 phosphorylates serine and threonine residues on target proteins. Reason: Correct annotation. Duplicates the IBA annotation with a different evidence code (IEA from combined automated methods). Having multiple independent lines of evidence is acceptable.
GO:0004679 AMP-activated protein kinase activity	IEA GO_REF:0000117	ACCEPT	Summary: This is the most specific molecular function annotation for AAK-2. It is supported by multiple IDA annotations from PMID:15574588 and PMID:29414769. Reason: Core molecular function. The IEA annotation is well-supported by experimental evidence (IDA) from the same gene.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: AAK-2 binds ATP for its kinase activity. This annotation is based on domain analysis. Reason: Correct annotation. AAK-2 contains the protein kinase ATP-binding signature (PROSITE PS00107) and requires ATP as a substrate for phosphotransferase activity.
GO:0005737 cytoplasm	IEA GO_REF:0000117	ACCEPT	Summary: Cytoplasmic localization annotation from ARBA machine learning. Duplicates the IBA and IDA annotations. Reason: Correct annotation, supported by experimental evidence from PMID:18408008. The multiple evidence codes (IBA, IDA, IEA) consistently support cytoplasmic localization.
GO:0016301 kinase activity	IEA GO_REF:0000043	ACCEPT	Summary: General kinase activity annotation inferred from UniProt keywords. Reason: Correct but highly general annotation. This is a parent term of the more specific protein kinase annotations. Retained as IEA.
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: Very general molecular function annotation. Kinases are a subtype of transferases. Reason: Correct but extremely general. This is a high-level parent term that adds little information beyond the more specific kinase annotations. Retained as standard IEA annotation.
GO:0043050 nematode pharyngeal pumping	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: AAK-2 is involved in pharyngeal pumping regulation. This is supported by experimental evidence in PMID:22768843 showing AAK-2 links serotonergic signaling to feeding behavior. Reason: This annotation is supported by experimental evidence (IMP from PMID:22768843). While valid, pharyngeal pumping regulation is a downstream physiological consequence of AAK-2's role in neuronal signaling rather than a core metabolic function. Supporting Evidence: PMID:22768843 neural serotonin signaling in C. elegans modulates feeding behavior through inhibition of AMP-activated kinase (AMPK) in interneurons
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	ACCEPT	Summary: Annotation from Rhea mapping. AAK-2 catalyzes serine phosphorylation reactions. Reason: Correct annotation. AAK-2 has protein serine kinase activity as part of its serine/threonine kinase function. Redundant with but consistent with GO:0004674.
GO:0120025 plasma membrane bounded cell projection	IEA GO_REF:0000117	MODIFY	Summary: General cellular component annotation. AAK-2 is localized to axons (PMID:18408008), which are plasma membrane bounded cell projections. Reason: This annotation is too general. The experimental evidence (PMID:18408008) specifically shows localization to axons (GO:0030424), which is a more specific child term. Proposed replacements: axon Supporting Evidence: PMID:18408008 expression of the AAK-2::green fluorescent protein fusion protein was observed in the ventral cord, some neurons
GO:0005515 protein binding	IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans...	MODIFY	Summary: Generic protein binding annotation from high-throughput protein-protein interaction study. The specific interactor is AAKB-2 (Q9NAH7), the AMPK beta subunit. Reason: Generic 'protein binding' annotations are discouraged in GO curation guidelines. The interaction with AAKB-2 reflects AAK-2's function as part of the AMPK complex. This should be captured through the 'part_of nucleotide-activated protein kinase complex' annotation (GO:0031588) rather than generic protein binding. Proposed replacements: nucleotide-activated protein kinase complex Supporting Evidence: PMID:19123269 We present an expanded C. elegans protein-protein interaction network, or 'interactome' map
GO:0004679 AMP-activated protein kinase activity	IDA PMID:29414769 High-glucose toxicity is mediated by AICAR-transformylase/IM...	ACCEPT	Summary: Direct experimental evidence for AMPK activity. The study shows AAK-2/AMPK mitigates high-glucose toxicity in C. elegans through its kinase activity. Reason: Core molecular function with direct experimental support. PMID:29414769 demonstrates that AMPK activity protects against glucose toxicity. Supporting Evidence: PMID:29414769 mitigated by AMP-activated protein kinase in Caenorhabditis elegans
GO:0007210 serotonin receptor signaling pathway	IMP PMID:22768843 AMP-activated kinase links serotonergic signaling to glutama...	KEEP AS NON CORE	Summary: AAK-2/AMPK functions downstream of serotonin signaling to regulate feeding behavior. The study shows AMPK links serotonergic signaling to glutamate release in interneurons. Reason: While AAK-2 participates in serotonin-mediated signaling cascades affecting feeding behavior, this is not a core function of AMPK but rather a context-specific role in C. elegans neurobiology. The annotation is supported by experimental evidence but represents a specialized function rather than the conserved core role. Supporting Evidence: PMID:22768843 neural serotonin signaling in C. elegans modulates feeding behavior through inhibition of AMP-activated kinase (AMPK) in interneurons
GO:0043050 nematode pharyngeal pumping	IMP PMID:22768843 AMP-activated kinase links serotonergic signaling to glutama...	KEEP AS NON CORE	Summary: Direct experimental evidence that AAK-2 affects pharyngeal pumping rate through its role in serotonergic signaling pathways. Reason: This is a C. elegans-specific phenotype annotation supported by experimental evidence. While valid, pharyngeal pumping regulation is a downstream physiological consequence of AAK-2's role in neuronal signaling rather than a core metabolic function. Retained as a non-core biological process. Supporting Evidence: PMID:22768843 AMP-activated kinase links serotonergic signaling to glutamate release for regulation of feeding behavior
GO:0050709 negative regulation of protein secretion	IMP PMID:28128367 A tachykinin-like neuroendocrine signalling axis couples cen...	ACCEPT	Summary: AAK-2/AMPK negatively regulates FLP-7 neuropeptide secretion from ASI neurons by keeping CRTC-1 (CREB co-activator) inactive through phosphorylation. Reason: Well-supported by experimental evidence. PMID:28128367 demonstrates that AAK-2 restrains FLP-7 secretion via CRTC-1 phosphorylation. Loss of aak-2 leads to increased FLP-7 secretion and fat loss. Supporting Evidence: PMID:28128367 in wild-type ASI neurons, AMPK signalling serves to keep the CREB co-regulator CRTC-1 inactive, which in turn restrains FLP-7 secretion
GO:0050714 positive regulation of protein secretion	IMP PMID:28128367 A tachykinin-like neuroendocrine signalling axis couples cen...	REMOVE	Summary: This annotation appears contradictory to GO:0050709. However, the study shows that 5-HT signaling de-represses CRTC-1 (by inhibiting AAK-2), which then stimulates FLP-7 secretion. The loss of AAK-2 activity leads to increased secretion. Reason: This annotation is misleading. AAK-2 is a negative regulator of protein secretion (GO:0050709). The 'positive regulation' effect observed is actually the consequence of AAK-2 loss or inhibition leading to de-repression of secretion. The annotation GO:0050709 (negative regulation of protein secretion) correctly captures AAK-2's function. This annotation confuses the phenotype of loss-of-function with the gene's actual function. Supporting Evidence: PMID:28128367 in wild-type ASI neurons, AMPK signalling serves to keep the CREB co-regulator CRTC-1 inactive, which in turn restrains FLP-7 secretion
GO:0004679 AMP-activated protein kinase activity	IDA PMID:15574588 The AMP-activated protein kinase AAK-2 links energy levels a...	ACCEPT	Summary: Foundational paper demonstrating AAK-2 AMPK activity. Shows AAK-2 is activated by AMP and functions as an energy sensor linking AMP:ATP ratios to lifespan. Reason: Core molecular function with direct experimental support. This is the foundational paper characterizing AAK-2 as a functional AMPK alpha subunit. Supporting Evidence: PMID:15574588 The C. elegans AMP-activated protein kinase alpha subunit AAK-2 is activated by AMP and functions to extend lifespan
GO:0061066 positive regulation of dauer larval development	IGI PMID:15574588 The AMP-activated protein kinase AAK-2 links energy levels a...	ACCEPT	Summary: AAK-2 promotes dauer development in interaction with insulin signaling pathway (daf-2). The IGI evidence indicates genetic interaction with daf-2. Reason: Well-supported annotation for a C. elegans-specific developmental process. AAK-2 functions in dauer regulation, linking energy status to developmental decisions. UniProt confirms: "Involved in the establishment of germline stem cell (GSC) quiescence during dauer development." Supporting Evidence: PMID:15574588 AAK-2 is a sensor that couples lifespan to information about energy levels and insulin-like signals
GO:0005737 cytoplasm	IDA PMID:18408008 The Caenorhabditis elegans AMP-activated protein kinase AAK-...	ACCEPT	Summary: Direct experimental evidence for cytoplasmic localization using AAK-2::GFP fusion protein. Reason: Strong experimental evidence. The AAK-2::GFP fusion protein was directly visualized in the cytoplasm of multiple cell types. Supporting Evidence: PMID:18408008 expression of the AAK-2::green fluorescent protein fusion protein was observed in the ventral cord, some neurons, body wall muscle, pharynx, vulva, somatic gonad, and excretory cell
GO:0030424 axon	IDA PMID:18408008 The Caenorhabditis elegans AMP-activated protein kinase AAK-...	ACCEPT	Summary: Direct experimental evidence for axonal localization of AAK-2 protein. Reason: Strong experimental evidence from GFP fusion protein visualization. This is consistent with AAK-2's role in axon regeneration. Supporting Evidence: PMID:18408008 expression of the AAK-2::green fluorescent protein fusion protein was observed in the ventral cord, some neurons
GO:0043025 neuronal cell body	IDA PMID:18408008 The Caenorhabditis elegans AMP-activated protein kinase AAK-...	ACCEPT	Summary: Direct experimental evidence for neuronal cell body localization of AAK-2 protein. Reason: Strong experimental evidence from GFP fusion protein visualization. Consistent with AAK-2's expression in neurons and neuronal functions. Supporting Evidence: PMID:18408008 expression of the AAK-2::green fluorescent protein fusion protein was observed in the ventral cord, some neurons
GO:0008340 determination of adult lifespan	IMP PMID:15574588 The AMP-activated protein kinase AAK-2 links energy levels a...	ACCEPT	Summary: Central finding of the paper: AAK-2 links energy sensing to lifespan regulation. aak-2 mutants have shortened lifespan. Reason: Core biological process annotation. This is a major characterized function of AAK-2 with strong experimental support from multiple studies. Supporting Evidence: PMID:15574588 AAK-2 is a sensor that couples lifespan to information about energy levels and insulin-like signals

Gene Description

Existing Annotations Review

Core Functions

AAK-2 is the catalytic alpha subunit of AMPK, providing the kinase activity that phosphorylates downstream substrates in response to energy stress.

AAK-2 functions as an energy sensor that couples cellular energy status (AMP:ATP ratio) to lifespan regulation. Loss of aak-2 shortens lifespan.

AAK-2 is the catalytic alpha subunit of the heterotrimeric AMPK complex, which includes beta and gamma regulatory subunits.

AAK-2/AMPK in ASI neurons phosphorylates CRTC-1 to keep it inactive, thereby restraining FLP-7 neuropeptide secretion and preventing fat loss.

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