PRKAA2 encodes the alpha-2 catalytic subunit of AMP-activated protein kinase (AMPK), a central cellular energy sensor that maintains energy homeostasis. As a serine/threonine kinase, PRKAA2 is activated when cellular AMP/ATP ratios rise, triggering phosphorylation of metabolic enzymes to suppress anabolic processes (fatty acid/cholesterol synthesis) while promoting catabolic processes (fatty acid oxidation, glycolysis, autophagy). The protein forms heterotrimeric complexes with regulatory beta and gamma subunits, localizes to both cytoplasm and nucleus, and phosphorylates key substrates including ACC (fatty acid synthesis), HMGCR (cholesterol synthesis), PFK-2 (glycolysis), and ChREBP (transcriptional regulation). Recent discoveries highlight its direct role in chromatin remodeling via histone H2B phosphorylation under stress conditions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core catalytic function strongly supported by extensive biochemical evidence. PRKAA2 phosphorylates serine/threonine residues on numerous substrates (ACC, HMGCR, PFK-2, ChREBP, TSC2, Raptor). Multiple IDA studies confirm this activity (PMID:8955377, PMID:12065578). Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research.md Generated using OpenAI Deep Research API file:rat/Prkaa2/Prkaa2-deep-research-falcon.md Prkaa2 encodes a **protein kinase** (EC 2.7.11.1; Ser/Thr kinase). |
| GO:0010508 positive regulation of autophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Well-established function through ULK1 phosphorylation and mTORC1 inhibition. However, 2024 research shows complexity - AMPK can suppress autophagy in specific contexts. Keep as important but context-dependent function. |
| GO:0042149 cellular response to glucose starvation | IBA GO_REF:0000033 | ACCEPT | Summary: Core function - AMPK is the primary cellular glucose/energy sensor. Activated by low glucose via AMP/ATP ratio changes. Knockout mice show impaired glucose homeostasis. Multiple ISS/ISO annotations support this. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMP binding to AMPK (via Ξ³ subunit CBS motifs) promotes AMPK activation through allosteric effects and protection from dephosphorylation, coupling ATP depletion to kinase activation. |
| GO:0006338 chromatin remodeling | IEA GO_REF:0000108 | ACCEPT | Summary: Supported by evidence that AMPK/PRKAA2 phosphorylates histone H2B under metabolic stress, linking energy sensing to chromatin remodeling. Reason: Chromatin remodeling is supported by histone H2B Ser36 phosphorylation in stress conditions, aligning with core_functions that capture this epigenetic regulation. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | REMOVE | Summary: Too general - more specific terms available (serine/threonine kinase, AMP-activated protein kinase). Redundant with better-annotated specific terms. |
| GO:0004679 AMP-activated protein kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core defining function of PRKAA2. Multiple IDA studies confirm (PMID:11069105, PMID:11724780, PMID:14511394). This is THE primary molecular function. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMP binding to AMPK (via Ξ³ subunit CBS motifs) promotes AMPK activation through allosteric effects and protection from dephosphorylation, coupling ATP depletion to kinase activation. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: Essential for kinase function - ATP is the phosphate donor. IDA evidence exists (PMID:16648175). Crystal structures confirm ATP-binding pocket. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md The Ξ± subunit provides the **catalytic kinase activity** and is activated primarily by phosphorylation at a conserved threonine within the activation loop (**Thr172 for Ξ±2**), which is a core mechanistic definition of βAMPK activation.β |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | REMOVE | Summary: Too general - ATP binding is more specific and already annotated. Redundant. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation consistent with IBA and IDA evidence. Core kinase function. |
| GO:0006325 chromatin organization | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Weak IEA evidence. While H2B phosphorylation occurs, this is stress-specific and not a primary function. Too broad. |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: Core function via ACC and HMGCR phosphorylation. Controls fatty acid and cholesterol synthesis. Strong experimental support (PMID:12065578). However, more specific terms available. |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: Core function - directly regulates ACC to control fatty acid synthesis/oxidation balance. IDA evidence for fatty acid homeostasis (PMID:11724780). |
| GO:0006633 fatty acid biosynthetic process | IEA GO_REF:0000043 | REMOVE | Summary: AMPK actually INHIBITS fatty acid synthesis by phosphorylating ACC. This annotation implies positive regulation which is incorrect. |
| GO:0006694 steroid biosynthetic process | IEA GO_REF:0000043 | REMOVE | Summary: Too broad and AMPK generally inhibits steroid/cholesterol synthesis. More specific negative regulation terms would be appropriate. |
| GO:0006695 cholesterol biosynthetic process | IEA GO_REF:0000043 | REMOVE | Summary: AMPK INHIBITS cholesterol synthesis via HMGCR phosphorylation. This term implies positive regulation which is incorrect. |
| GO:0006914 autophagy | IEA GO_REF:0000043 | REMOVE | Summary: Too broad - 'positive regulation of autophagy' is more accurate. Complex bidirectional regulation discovered in 2024. |
| GO:0008202 steroid metabolic process | IEA GO_REF:0000043 | REMOVE | Summary: Too broad. AMPK's role is more specific to cholesterol metabolism inhibition. |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: AMPK regulates cholesterol metabolism primarily through HMGCR inhibition. Keep but note the regulatory direction. Reason: PRKAA2 directly phosphorylates and inhibits HMGCR, making cholesterol metabolism a core regulated process in energy stress. |
| GO:0016055 Wnt signaling pathway | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Weak evidence, likely indirect effect. May phosphorylate beta-catenin but not a primary function. IEA only. |
| GO:0016126 sterol biosynthetic process | IEA GO_REF:0000043 | REMOVE | Summary: AMPK inhibits rather than promotes sterol synthesis. Misleading annotation. |
| GO:0016301 kinase activity | IEA GO_REF:0000043 | REMOVE | Summary: Too general - more specific terms (protein serine/threonine kinase, AMP-activated protein kinase) are already annotated. |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | REMOVE | Summary: Far too general - specific kinase terms already present. No value added. |
| GO:0031000 response to caffeine | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IDA evidence exists (PMID:19608206) showing caffeine activates AMPK in muscle. However, this is a pharmacological response, not a core function. |
| GO:0045821 positive regulation of glycolytic process | IEA GO_REF:0000117 | ACCEPT | Summary: Core function - AMPK phosphorylates PFK-2 at Ser466 to activate glycolysis. Strong IDA evidence (PMID:11069105). Critical for ATP generation under stress. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: Mg2+ binding is required for kinase activity (coordinates ATP). Standard feature of protein kinases. Could be more specific. Proposed replacements: magnesium ion binding |
| GO:0047322 [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Specific substrate phosphorylation well-documented (PMID:2369897). Important for cholesterol homeostasis. Keep as it provides mechanistic specificity. |
| GO:0048511 rhythmic process | IEA GO_REF:0000043 | REMOVE | Summary: Too vague. 'Regulation of circadian rhythm' is more specific and has better evidence. Redundant. |
| GO:0055089 fatty acid homeostasis | IEA GO_REF:0000117 | ACCEPT | Summary: Core function with strong IDA evidence (PMID:11724780). AMPK balances fatty acid synthesis/oxidation via ACC phosphorylation. |
| GO:0071277 cellular response to calcium ion | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: AMPK is activated by CaMKK2 in response to calcium. IMP evidence exists (PMID:25788287). Important regulatory mechanism but not primary function. |
| GO:0071333 cellular response to glucose stimulus | IEA GO_REF:0000117 | ACCEPT | Summary: Core function - responds to both high and low glucose. IMP evidence (PMID:25788287). Central to glucose homeostasis. |
| GO:0097009 energy homeostasis | IEA GO_REF:0000117 | ACCEPT | Summary: THE core function of AMPK - master regulator of cellular energy balance. Strong IDA evidence (PMID:11724780). Fundamental role. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md Functionally, AMPKΞ±2 integrates energy stress to inhibit anabolic metabolism and promote catabolism and autophagy |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | REMOVE | Summary: Redundant with 'protein serine/threonine kinase activity' which is more complete and has better evidence. |
| GO:0031669 cellular response to nutrient levels | ISO GO_REF:0000096 | ACCEPT | Summary: Core function - AMPK senses and responds to nutrient availability. Strong ISO evidence from mouse. Fundamental role in metabolism. RETIRED - GO_REF:0000096 no longer used in GOA. |
| GO:0004679 AMP-activated protein kinase activity | ISO GO_REF:0000096 | ACCEPT | Summary: Duplicate annotation - core AMPK function already reviewed as IBA evidence type. This ISO annotation provides additional ortholog-based support for the same function. RETIRED - GO_REF:0000096 no longer used in GOA. |
| GO:0004674 protein serine/threonine kinase activity | ISO GO_REF:0000096 | ACCEPT | Summary: Ortholog-based annotation consistent with IBA and IDA evidence. Core kinase function. RETIRED - GO_REF:0000096 no longer used in GOA. |
| GO:0140823 histone H2BS36 kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Evidence for H2B Ser36 phosphorylation by AMPK under stress conditions is well-established in mammals. This is a specific stress-response function supported by experimental data. |
| GO:0140823 histone H2BS36 kinase activity | ISO GO_REF:0000096 | ACCEPT | Summary: Ortholog evidence for H2B Ser36 phosphorylation under stress conditions. |
| GO:0004679 AMP-activated protein kinase activity | IMP PMID:25788287 Polarized activities of AMPK and BRSK in primary hippocampal... | ACCEPT | Summary: Strong evidence - PMID:25788287 shows calcium-dependent AMPK activation in neurons. IMP evidence for core AMPK function. Supporting Evidence: PMID:25788287 Polarized activities of AMPK and BRSK in primary hippocampal neurons |
| GO:0042149 cellular response to glucose starvation | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity evidence for glucose starvation response. Core AMPK function. |
| GO:0042149 cellular response to glucose starvation | ISO GO_REF:0000096 | ACCEPT | Summary: Ortholog evidence for glucose starvation response. Core AMPK function. |
| GO:1905691 lipid droplet disassembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: AMPK promotes lipolysis and lipid droplet breakdown via phosphorylation of lipases and metabolic enzymes. This is supported by evidence of AMPK activating lipid oxidation pathways. |
| GO:1905691 lipid droplet disassembly | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Ortholog evidence for AMPK role in lipid droplet breakdown. |
| GO:0062028 regulation of stress granule assembly | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: AMPK responds to stress conditions and may influence stress granule formation, but evidence is indirect. Likely over-annotation as not a primary function. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SOURCE WEAK OR INFERRED Retired GO_REF:0000096 row; the donor is read from the surviving equivalent ISO row. Mouse Prkaa2 support for this term is an IGI (PMID:27430620) plus IEA, which is indirect evidence for a regulatory role. |
| GO:0010629 negative regulation of gene expression | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: AMPK negatively regulates lipogenic genes (ChREBP, SREBP) and anabolic gene programs. However, term is too broad - more specific terms would be better. |
| GO:0034599 cellular response to oxidative stress | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: AMPK is activated during oxidative stress and promotes protective responses including autophagy. This is a legitimate stress response function. |
| GO:0070507 regulation of microtubule cytoskeleton organization | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: Weak evidence - AMPK may indirectly affect cytoskeleton but this is not a well-established primary function. Likely over-annotation. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SOURCE WEAK OR INFERRED Retired GO_REF:0000096 row; the donor is read from the surviving equivalent ISO row. Mouse donor support is IGI-only (PMID:27430620), too indirect to establish a cytoskeletal regulatory role. |
| GO:0071277 cellular response to calcium ion | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Ortholog evidence for calcium-dependent AMPK activation. Important regulatory mechanism. |
| GO:0071277 cellular response to calcium ion | IMP PMID:25788287 Polarized activities of AMPK and BRSK in primary hippocampal... | KEEP AS NON CORE | Summary: Strong evidence - PMID:25788287 demonstrates calcium-dependent AMPK activation via CaMKK2 pathway. Important regulatory mechanism but not core metabolic function. Supporting Evidence: PMID:25788287 2015 Mar 18. Polarized activities of AMPK and BRSK in primary hippocampal neurons. |
| GO:0071333 cellular response to glucose stimulus | ISO GO_REF:0000096 | ACCEPT | Summary: Ortholog evidence for glucose response. Core AMPK function. |
| GO:0071333 cellular response to glucose stimulus | IMP PMID:25788287 Polarized activities of AMPK and BRSK in primary hippocampal... | ACCEPT | Summary: Strong supporting evidence for core glucose sensing function. IMP evidence adds to already accepted IEA annotation. Supporting Evidence: PMID:25788287 Polarized activities of AMPK and BRSK in primary hippocampal neurons |
| GO:0010468 regulation of gene expression | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Too broad - AMPK regulates specific gene sets via ChREBP, SREBP, p53, etc. More specific terms would be preferable. |
| GO:0014850 response to muscle activity | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Well-established function - AMPK is activated during muscle contraction and exercise. Important for muscle energy metabolism adaptation. |
| GO:0071466 cellular response to xenobiotic stimulus | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: AMPK can be activated by xenobiotics like AICAR, metformin, and other compounds. Secondary response, not core function. |
| GO:0016241 regulation of macroautophagy | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: More specific than general autophagy term. AMPK regulates macroautophagy via ULK1 phosphorylation and mTORC1 inhibition. Established function. |
| GO:0016241 regulation of macroautophagy | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Ortholog evidence for macroautophagy regulation. Established function. |
| GO:0071380 cellular response to prostaglandin E stimulus | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: Very specific response that may occur but is not well-documented as primary function. Likely over-annotation. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH GRANULARITY MISMATCH Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS SOURCE BUT NOT TARGET Retired GO_REF:0000096 row; the donor is read from the surviving equivalent ISO row. The mouse IGI (PMID:23479225) is a narrow stimulus-specific observation that does not generalise to a rat gene-level annotation. |
| GO:0004712 protein serine/threonine/tyrosine kinase activity | ISO GO_REF:0000096 | REMOVE | Summary: AMPK is primarily serine/threonine kinase, not tyrosine. This broader term is less accurate than the specific serine/threonine kinase annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P54646 Β· human PRKAA2 SUPPORTS SOURCE BUT NOT TARGET Retired GO_REF:0000096 row; the donor is read from the surviving equivalent ISO row. Human PRKAA2 does carry this term (IDA, PMID:22797923), but the combined Ser/Thr/Tyr term is broader than the rat enzyme's serine/threonine activity. |
| GO:0003682 chromatin binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: AMPK translocates to nucleus under stress and binds chromatin to phosphorylate histones. Evidence from H2B phosphorylation studies supports this. |
| GO:0003682 chromatin binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Ortholog evidence for chromatin binding during stress responses. |
| GO:0004679 AMP-activated protein kinase activity | IDA PMID:11069105 Phosphorylation and activation of heart PFK-2 by AMPK has a ... | ACCEPT | Summary: Strong direct evidence for core AMPK function. PMID:11069105 demonstrates AMPK phosphorylation of PFK-2, confirming kinase activity. Supporting Evidence: PMID:11069105 Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia |
| GO:0004679 AMP-activated protein kinase activity | IDA PMID:11724780 Mechanism for fatty acid "sparing" effect on glucose-induced... | ACCEPT | Summary: Strong direct evidence for core AMPK function. PMID:11724780 demonstrates AMPK phosphorylation of ChREBP, confirming kinase activity. Supporting Evidence: PMID:11724780 Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase |
| GO:0005515 protein binding | IPI PMID:11069105 Phosphorylation and activation of heart PFK-2 by AMPK has a ... | REMOVE | Summary: Too general - AMPK binds many proteins but more specific terms would be better (complex binding, substrate binding). Remove as uninformative. Supporting Evidence: PMID:11069105 Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. |
| GO:0005515 protein binding | IPI PMID:11724780 Mechanism for fatty acid "sparing" effect on glucose-induced... | REMOVE | Summary: Too general - AMPK binds many proteins but more specific terms would be better. Remove as uninformative. Supporting Evidence: PMID:11724780 Nov 27. Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. |
| GO:0008610 lipid biosynthetic process | ISS GO_REF:0000024 | REMOVE | Summary: Misleading - AMPK actually INHIBITS lipid biosynthesis by phosphorylating ACC and other enzymes. This should be negative regulation. |
| GO:0008610 lipid biosynthetic process | ISO GO_REF:0000096 | REMOVE | Summary: Misleading - AMPK actually INHIBITS lipid biosynthesis (by phosphorylating and inactivating ACC and other lipogenic enzymes), so it does not execute a function within this process. The donor annotations are experimentally grounded (mouse IDA, PMID:21459323; human ISS/IEA), so the defect is the term's regulatory-sign/role conflation, not a missing source; the biology is captured by the negative-regulation rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS SOURCE BUT NOT TARGET Retired GO_REF:0000096 row; the donor is read from the surviving equivalent ISO row. The mouse donor has an IDA for this term (PMID:21459323), but AMPK's role in lipid biosynthesis is regulatory (largely inhibitory) rather than participation in the process. |
| GO:0010508 positive regulation of autophagy | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence similarity evidence for autophagy regulation. Complex context-dependent function. |
| GO:0010508 positive regulation of autophagy | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Ortholog evidence for autophagy regulation. Complex context-dependent function. |
| GO:0031669 cellular response to nutrient levels | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity evidence for nutrient sensing. Core AMPK function. |
| GO:0032007 negative regulation of TOR signaling | ISS GO_REF:0000024 | ACCEPT | Summary: Core function - AMPK inhibits mTORC1 via TSC2 and Raptor phosphorylation. Well-established mechanism for energy conservation. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPK inhibits mTORC1 via phosphorylation of TSC2 and Raptor |
| GO:0032007 negative regulation of TOR signaling | ISO GO_REF:0000096 | ACCEPT | Summary: Ortholog evidence for TOR inhibition. Core metabolic regulation. |
| GO:0042752 regulation of circadian rhythm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: AMPK phosphorylates CRY1 and links metabolism to circadian rhythms. However, this is not a primary metabolic function. |
| GO:0042752 regulation of circadian rhythm | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Ortholog evidence for circadian regulation via CRY1 phosphorylation. |
| GO:0043066 negative regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: AMPK can promote cell survival during mild stress via autophagy and p53 phosphorylation. Context-dependent protective function. |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Ortholog evidence for cell survival promotion during stress. |
| GO:0045821 positive regulation of glycolytic process | IDA PMID:11069105 Phosphorylation and activation of heart PFK-2 by AMPK has a ... | ACCEPT | Summary: Strong direct evidence - PMID:11069105 demonstrates AMPK phosphorylation of PFK-2 which activates glycolysis. Core metabolic function. Supporting Evidence: PMID:11069105 Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia |
| GO:0055089 fatty acid homeostasis | IDA PMID:11724780 Mechanism for fatty acid "sparing" effect on glucose-induced... | ACCEPT | Summary: Strong direct evidence - PMID:11724780 shows AMPK regulation of fatty acid metabolism via ACC phosphorylation. Core function already accepted from IEA. Supporting Evidence: PMID:11724780 Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase |
| GO:0097009 energy homeostasis | IDA PMID:11724780 Mechanism for fatty acid "sparing" effect on glucose-induced... | ACCEPT | Summary: Strong direct evidence - PMID:11724780 demonstrates AMPK role in cellular energy balance. THE core function already accepted from IEA. Supporting Evidence: PMID:11724780 Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase |
| GO:0042593 glucose homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Core function - AMPK is central to glucose homeostasis through multiple mechanisms. Well-established role in glucose metabolism. |
| GO:0042593 glucose homeostasis | ISO GO_REF:0000096 | ACCEPT | Summary: Ortholog evidence for glucose homeostasis. Core metabolic function. |
| GO:0014823 response to activity | IDA PMID:17253964 Adrenaline is a critical mediator of acute exercise-induced ... | KEEP AS NON CORE | Summary: PMID:17253964 shows adrenergic activation of AMPK in adipocytes during activity. Important physiological response but not core function. Supporting Evidence: PMID:17253964 Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes. |
| GO:0031000 response to caffeine | IDA PMID:19608206 Caffeine acutely activates 5'adenosine monophosphate-activat... | KEEP AS NON CORE | Summary: Strong direct evidence - PMID:19608206 shows caffeine activates AMPK in skeletal muscle. Pharmacological response already accepted from IEA. Supporting Evidence: PMID:19608206 2009 Jul 15. Caffeine acutely activates 5'adenosine monophosphate-activated protein kinase and increases insulin-independent glucose transport in rat skeletal muscles. |
| GO:0004679 AMP-activated protein kinase activity | IDA PMID:14511394 Complexes between the LKB1 tumor suppressor, STRAD alpha/bet... | ACCEPT | Summary: Strong direct evidence - PMID:14511394 demonstrates AMPK complexes and upstream kinase LKB1. Direct confirmation of kinase activity. Supporting Evidence: PMID:14511394 Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade |
| GO:0044877 protein-containing complex binding | IDA PMID:14511394 Complexes between the LKB1 tumor suppressor, STRAD alpha/bet... | KEEP AS NON CORE | Summary: PMID:14511394 shows AMPK interaction with LKB1-STRD-MO25 complex. Specific complex binding is more informative than general protein binding. Supporting Evidence: PMID:14511394 Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:8955377 The alpha1 and alpha2 isoforms of the AMP-activated protein ... | ACCEPT | Summary: Strong direct evidence - PMID:8955377 demonstrates substrate specificity differences between Ξ±1 and Ξ±2 isoforms. Core kinase function. Supporting Evidence: PMID:8955377 The alpha1 and alpha2 isoforms of the AMP-activated protein kinase have similar activities in rat liver but exhibit differences in substrate specificity in vitro. |
| GO:0004679 AMP-activated protein kinase activity | IMP PMID:10698692 Characterization of AMP-activated protein kinase gamma-subun... | ACCEPT | Summary: IMP evidence from Ξ³ subunit characterization study. Shows requirement for Ξ³ subunit in AMP binding and AMPK activation. Supporting Evidence: PMID:10698692 Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding |
| GO:0004679 AMP-activated protein kinase activity | IMP PMID:8955377 The alpha1 and alpha2 isoforms of the AMP-activated protein ... | ACCEPT | Summary: IMP evidence showing differential properties of Ξ±2 vs Ξ±1 complexes. Demonstrates AMP-activation specifically. Supporting Evidence: PMID:8955377 The alpha1 and alpha2 isoforms of the AMP-activated protein kinase have similar activities in rat liver but exhibit differences in substrate specificity in vitro. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:15695819 AMP-activated protein kinase beta subunit tethers alpha and ... | REMOVE | Summary: PMID:15695819 shows Ξ² subunit tethering Ξ± and Ξ³ subunits. However, this refers to Ξ² subunit function, not Ξ±2 directly. Supporting Evidence: PMID:15695819 2005 Jan 28. AMP-activated protein kinase beta subunit tethers alpha and gamma subunits via its C-terminal sequence (186-270). |
| GO:0004679 AMP-activated protein kinase activity | IDA PMID:16648175 Activation of AMPK alpha- and gamma-isoform complexes in the... | ACCEPT | Summary: Strong direct evidence - PMID:16648175 shows AMPK activation in ischemic heart. Direct biochemical demonstration of kinase activity. Supporting Evidence: PMID:16648175 Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart |
| GO:0005515 protein binding | IPI PMID:16648175 Activation of AMPK alpha- and gamma-isoform complexes in the... | REMOVE | Summary: Too general - while AMPK binds proteins, more specific terms are preferable. Remove as uninformative. Supporting Evidence: PMID:16648175 Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart. |
| GO:0005524 ATP binding | IDA PMID:16648175 Activation of AMPK alpha- and gamma-isoform complexes in the... | ACCEPT | Summary: Strong evidence - PMID:16648175 demonstrates ATP requirement for AMPK activity. Core function already accepted from IEA. Supporting Evidence: PMID:16648175 Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart |
| GO:0004672 protein kinase activity | IDA PMID:12065578 Coordinate regulation of malonyl-CoA decarboxylase, sn-glyce... | REMOVE | Summary: Too general - more specific serine/threonine and AMP-activated kinase terms already accepted. Remove redundant broad term. Supporting Evidence: PMID:12065578 2002 Jun 13. Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. |
| GO:0019216 regulation of lipid metabolic process | IDA PMID:12065578 Coordinate regulation of malonyl-CoA decarboxylase, sn-glyce... | ACCEPT | Summary: Strong evidence - PMID:12065578 shows AMPK regulation of ACC and other lipid metabolic enzymes. Well-established function. Supporting Evidence: PMID:12065578 Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: AMPK localizes to both cytoplasm and nucleus depending on cellular conditions. Nuclear localization is particularly important for its histone H2B phosphorylation function and direct transcriptional regulation under stress conditions. The Ξ±2 subunit can translocate to nucleus where it phosphorylates chromatin targets and interacts with transcriptional machinery. Reason: Nuclear localization is essential for AMPK's stress-responsive chromatin modifying activities and direct transcriptional regulation, representing a key aspect of its energy-sensing function beyond cytoplasmic metabolism. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: The cytoplasm is the primary location for AMPK's core metabolic regulatory functions. Here AMPK phosphorylates key metabolic enzymes including ACC (fatty acid synthesis), PFK-2 (glycolysis), HMGCR (cholesterol synthesis), and TSC2/Raptor (mTORC1 signaling). The majority of AMPK's energy-sensing and metabolic control activities occur in this compartment. Reason: Cytoplasmic localization is fundamental to AMPK's primary role as a metabolic energy sensor. Most of its well-characterized substrate phosphorylation events occur in the cytoplasm where metabolic enzymes and signaling complexes are located. |
| GO:1904262 negative regulation of TORC1 signaling | IBA GO_REF:0000033 | ACCEPT | Summary: AMPK directly inhibits mTORC1 by phosphorylating TSC2 and Raptor, a well-established energy-conservation mechanism. This TORC1-specific term is more precise than the generic negative regulation of TOR signaling annotation and reflects a core downstream signaling role. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPK inhibits mTORC1 via phosphorylation of TSC2 and Raptor |
| GO:1990044 protein localization to lipid droplet | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT-propagated annotation seeded by experimentally grounded human AMPK alpha subunits (UniProtKB:P54646, Q13131) and mouse family members. AMPK regulates lipid droplet dynamics (the companion ISO annotation to lipid droplet disassembly was kept as non-core), and directing proteins to lipid droplets is a defensible but contextual output of AMPK signaling rather than the core energy-sensing kinase function. Reason: The phylogenetic placement is plausible and the biology (AMPK control of lipid droplet-associated proteins during lipolysis/lipid mobilization) is real, but it is a downstream, context-dependent role. Core function remains AMP-activated protein kinase activity in energy homeostasis; kept as non-core consistent with the lipid droplet disassembly ISO row. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN001217983 Β· PANTHER:PTN001217983 SUPPORTS TRANSFER PAINT node for the AMPK catalytic alpha subunits; lipid-droplet protein targeting is experimentally grounded in the clade (human and mouse alpha subunits, IDA PMID:34077757), but it is a downstream, context-dependent output, hence non-core. |
| GO:0031588 nucleotide-activated protein kinase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Core complex membership - AMPKalpha2 is the catalytic subunit of the heterotrimeric AMP-activated protein kinase complex (alpha-beta-gamma), which is exactly what this term denotes. Direct rat IDA evidence exists for the same term (PMID:16648175), and the target's own RGD record is among the descendant evidences behind the PAINT IBD, so the IBA adds the phylogenetic statement that heterotrimer membership is ancestral. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001217983 Β· PANTHER:PTN001217983 SUPPORTS TRANSFER PAINT node for the AMPK catalytic alpha subunits; heterotrimeric complex membership is conserved throughout the clade and independently supported on the rat gene by IDA (PMID:16648175). Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research.md It resides in the **βnucleotide-activated protein kinase complexβ** (AMPK heterotrimer) within the cytoplasm and can translocate to the nucleus upon activation PMID:16648175 AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic alpha-subunits and regulatory beta- and gamma-subunits with multiple isoforms |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation consistent with experimental evidence. Nuclear localization supports stress-responsive functions including histone phosphorylation and transcriptional regulation. Reason: Supports the manually curated IBA annotation with additional automated evidence for nuclear localization. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation consistent with experimental evidence. Cytoplasmic localization is where AMPK performs most of its metabolic regulatory functions through substrate phosphorylation. Reason: Supports the manually curated IBA annotation with additional automated evidence for cytoplasmic localization. |
| GO:0030424 axon | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation corroborated by direct rat IMP evidence (PMID:25788287) showing AMPK activity in axons of primary hippocampal neurons. Real localization, but a neuron-specific subcellular context rather than the core site of AMPK's metabolic regulatory function. Reason: Consistent with the IMP and ISO annotations for the same term; axonal localization reflects where the broadly expressed kinase resides in neurons, not a distinct core function. Kept as non-core alongside the other neuronal compartment terms. Supporting Evidence: PMID:25788287 AMPK activity is stimulated by either Ca(2+) or 2-DG in the soma, dendrites, and axons of hippocampal neurons, with maximal stimulated activity observed in the distal region of the axon |
| GO:0030425 dendrite | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation corroborated by direct rat IMP evidence (PMID:25788287) showing AMPK activity in dendrites of primary hippocampal neurons. Real localization, but a neuron-specific context rather than a core functional site. Reason: Consistent with the IMP and ISO annotations for the same term; dendritic localization is a cell-type-specific distribution of the broadly expressed kinase, kept as non-core. Supporting Evidence: PMID:25788287 AMPK activity is stimulated by either Ca(2+) or 2-DG in the soma, dendrites, and axons of hippocampal neurons, with maximal stimulated activity observed in the distal region of the axon |
| GO:0031588 nucleotide-activated protein kinase complex | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation consistent with the IBA, ISO and direct rat IDA (PMID:16648175) evidence that AMPKalpha2 is the catalytic subunit of the heterotrimeric AMPK complex. Core complex membership. Supporting Evidence: PMID:16648175 AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic alpha-subunits and regulatory beta- and gamma-subunits with multiple isoforms |
| GO:0043025 neuronal cell body | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation corroborated by direct rat IMP evidence (PMID:25788287) showing AMPK activity in the soma of primary hippocampal neurons. Real localization, but a neuron-specific context rather than a core functional site. Reason: Consistent with the IMP and ISO annotations for the same term; somatic localization in neurons is a cell-type-specific distribution of the broadly expressed kinase, kept as non-core. Supporting Evidence: PMID:25788287 AMPK activity is stimulated by either Ca(2+) or 2-DG in the soma, dendrites, and axons of hippocampal neurons, with maximal stimulated activity observed in the distal region of the axon |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: Ortholog-based annotation from mouse-rat comparisons. Nuclear localization is conserved across mammalian AMPK Ξ±2 subunits for stress-responsive chromatin functions. Reason: Strong orthology evidence supports nuclear localization, consistent with other annotation types. |
| GO:0031588 nucleotide-activated protein kinase complex | ISO GO_REF:0000121 | ACCEPT | Summary: RGD ISO transfer from human PRKAA2 (UniProtKB:P54646). Human and rat alpha2 subunits assemble identical heterotrimeric AMPK complexes, and direct rat IDA evidence for this term exists (PMID:16648175). Core complex membership. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SUPPORTS TRANSFER Human PRKAA2 carries this term with direct interaction evidence (IPI, e.g. PMID:9693118) and assembles the same alpha-beta-gamma complex as the rat alpha2 subunit. Supporting Evidence: PMID:16648175 AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic alpha-subunits and regulatory beta- and gamma-subunits with multiple isoforms |
| GO:0031669 cellular response to nutrient levels | ISO GO_REF:0000121 | ACCEPT | Summary: ISO annotation consistent with curated evidence for this term. |
| GO:0004679 AMP-activated protein kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO annotation consistent with curated evidence for this term. |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Ortholog-transferred localization consistent with the accepted cytoplasm annotations (IDA, IEA, ISO). AMPKalpha2 is predominantly a cytosolic kinase, where it phosphorylates its principal metabolic substrates (ACC, HMGCR, TSC2/Raptor). Reason: Cytosolic localization is the primary site of AMPK's metabolic regulatory function; consistent with the accepted cytoplasm rows. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SUPPORTS TRANSFER Human PRKAA2 cytosol annotation (Reactome TAS and IEA) matches the rat IDA/IEA cytoplasm rows. MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS TRANSFER Mouse Prkaa2 carries a direct cytosol annotation (IDA, PMID:30201684), independently supporting the transferred localisation. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research.md The AMPKΞ±2 protein is predominantly a **cytosolic kinase**, but it dynamically localizes to multiple cellular compartments |
| GO:0005654 nucleoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Ortholog-transferred localization from human PRKAA2. AMPKalpha2 carries a nuclear localization signal, shuttles to the nucleus, and has nuclear substrates (histone H2B Ser36, ChREBP), so nucleoplasmic localization is well grounded and consistent with the accepted nucleus annotations. Reason: Consistent with accepted nucleus IEA/ISO rows and the Reactome TAS nucleoplasm annotations; nuclear localization underlies the chromatin/transcriptional arm of AMPKalpha2 function. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SUPPORTS TRANSFER Human PRKAA2 nucleoplasm annotation is a large-scale localisation IDA (GO_REF:0000052), consistent with AMPKalpha2 nuclear shuttling and its nuclear substrates. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPKΞ±2 contains a nuclear localization signal and can shuttle to the nucleus |
| GO:0005794 Golgi apparatus | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred localization from human PRKAA2, most likely deriving from high-throughput antibody-based localization data. Golgi localization of AMPKalpha2 has no support in the reviewed literature or either deep-research synthesis, which place the kinase in cytosol, nucleus, and at lysosomal/organelle signaling sites - not the Golgi. Reason: Not demonstrably wrong (transient organelle-surface pools of AMPK exist), but uncorroborated by any focused study and absent from the gene's functional literature; likely an over-annotation from a transferred high-throughput observation. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING The current human PRKAA2 record carries no Golgi apparatus annotation (QuickGO, checked 2026-08), so the transferred localisation can no longer be checked against the donor and is uncorroborated in the AMPK literature. |
| GO:0016607 nuclear speck | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ortholog-transferred localization from human PRKAA2. Activated AMPKalpha2 has been reported at nuclear speckles, in line with its nuclear shuttling and transcription/chromatin-associated functions, but this is a fine-grained localization observation rather than a core functional site. Reason: Compatible with the accepted nucleus/nucleoplasm annotations, but speckle localization is a specialized observation without an established functional role for AMPKalpha2; kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SUPPORTS TRANSFER Human PRKAA2 nuclear speck annotation is a large-scale localisation IDA (GO_REF:0000052) plus IEA; a fine-grained localisation observation rather than a core functional site. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research.md Activated AMPKΞ±2 has been observed in the **nucleoplasm** and even at **nuclear speckles**, consistent with its role in regulating transcription and chromatin remodeling |
| GO:0036064 ciliary basal body | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ortholog-transferred localization from human PRKAA2. A basal-body pool of AMPK (linked to LKB1 signaling from the cilium) has been reported in mammalian cells, but it is a specialized, context-dependent localization not covered in the reviewed literature for the rat gene and peripheral to AMPKalpha2's core energy-sensing role. Reason: Plausible transferred localization for a kinase with several organelle-associated signaling pools, but contextual and uncorroborated in rat; kept as non-core rather than core localization. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING The current human PRKAA2 record no longer carries ciliary basal body (QuickGO, checked 2026-08); the transferred localisation cannot be re-verified on the donor and remains a specialised, context-dependent claim. |
| GO:1904262 negative regulation of TORC1 signaling | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity support for AMPK-mediated inhibition of mTORC1 via TSC2/Raptor phosphorylation. Consistent with the curated IBA annotation for this TORC1-specific term. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPK inhibits mTORC1 via phosphorylation of TSC2 and Raptor |
| GO:1904262 negative regulation of TORC1 signaling | ISO GO_REF:0000121 | ACCEPT | Summary: Ortholog-based support for AMPK-mediated inhibition of mTORC1. Consistent with the curated IBA/ISS annotations for this TORC1-specific term. |
| GO:0002181 cytoplasmic translation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Ortholog transfer from human PRKAA2 with an acts_upstream_of_or_within qualifier. AMPK is an upstream regulator of translation (suppressing initiation via mTORC1/TSC2/Raptor under energy stress), not a component of the cytoplasmic translation machinery. Annotating the regulator to the direct process term adds nothing beyond the co-annotated regulation-of-translational-initiation terms. Reason: The regulatory relationship is real but is already captured more precisely by negative regulation of translational initiation and negative regulation of TORC1 signaling; the direct process term over-states AMPK's role in translation itself. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); the rat row's acts_upstream_of_or_within qualifier already indicates regulation of translation rather than participation in it. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPK inhibits mTORC1 via phosphorylation of TSC2 and Raptor |
| GO:0009267 cellular response to starvation | ISO GO_REF:0000121 | ACCEPT | Summary: Ortholog transfer from human PRKAA2. Responding to nutrient/energy deprivation is the defining physiological context of AMPK activation; this parent term is fully consistent with the accepted cellular response to glucose starvation (IBA/ISO) and cellular response to nutrient levels annotations. Reason: Core stress-response context of AMPKalpha2 - starvation raises AMP/ADP and triggers Thr172 phosphorylation and downstream metabolic reprogramming; consistent with the accepted child-term rows. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08), although starvation-triggered activation is amply supported for AMPK by other rows on the rat gene. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md Functionally, AMPKΞ±2 integrates energy stress to inhibit anabolic metabolism and promote catabolism and autophagy |
| GO:0034198 cellular response to amino acid starvation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ortholog transfer from human PRKAA2. AMPK participates in starvation responses generally, but amino-acid deprivation sensing is canonically GCN2/mTORC1 territory; AMPK's primary inputs are energy/glucose stress. Amino-acid-starvation contexts engage AMPK secondarily (e.g. via lysosomal nutrient-sensing signaling), so this is defensible but not core. Reason: Kept as non-core - the specific amino-acid starvation response is a contextual engagement of AMPK within lysosome-centered nutrient signaling rather than its defining glucose/energy-stress input, which is captured by the accepted glucose-starvation terms. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); amino-acid starvation is in any case a secondary context for AMPK relative to energy/glucose stress. |
| GO:0038202 TORC1 signaling | ISO GO_REF:0000121 | MODIFY | Summary: Ortholog transfer from human PRKAA2 with an acts_upstream_of_or_within qualifier. AMPK acts on TORC1 signaling strictly as an upstream negative regulator (phosphorylating TSC2 and Raptor); the direction-neutral process term is less informative than the already-accepted negative regulation of TORC1 signaling (GO:1904262, IBA/ISS/ISO). Reason: The essence (AMPK impinging on TORC1 signaling) is sound, but the regulatory-direction-specific term is the right level of description and is already independently annotated; replace the generic process term with it. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08), which instead carries negative regulation of TOR signaling (GO:0032007) - the direction-specific term that better describes the donor evidence. Proposed replacements: negative regulation of TORC1 signaling Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPK inhibits mTORC1 via phosphorylation of TSC2 and Raptor |
| GO:0042149 cellular response to glucose starvation | ISO GO_REF:0000121 | ACCEPT | Summary: ISO annotation consistent with curated evidence for this term. |
| GO:0045947 negative regulation of translational initiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ortholog transfer from human PRKAA2. Suppression of cap-dependent translational initiation is a well-established downstream output of AMPK activation, mediated through inhibition of mTORC1 (TSC2/Raptor phosphorylation) and consequent 4E-BP1/S6K dephosphorylation under energy stress. Reason: Biologically sound, but it is an indirect consequence of the core function (negative regulation of TORC1 signaling) rather than a direct AMPK activity on initiation factors; kept as non-core, consistent with the acts_upstream_of_or_within qualifier in GOA. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); suppression of initiation follows indirectly from the donor's negative regulation of TOR signaling (GO:0032007, ISS/IEA). Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPK inhibits mTORC1 via phosphorylation of TSC2 and Raptor |
| GO:0045948 positive regulation of translational initiation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Ortholog transfer from human PRKAA2 asserting the opposite direction to AMPK's canonical suppression of translational initiation under energy stress. Positive effects on initiation are, at most, reported for specific mRNAs in specific contexts; the underlying human evidence cannot be traced from this ISO row, and no support appears in the reviewed literature or deep-research syntheses. Reason: Not necessarily wrong in its original context (the GOA qualifier is acts_upstream_of_or_within, and both directions are annotated on the human source), but as a transferred gene-level claim it conflicts with the canonical mTORC1-mediated suppression of initiation and likely over-represents a context-specific observation. The companion negative regulation row is retained (non-core) instead. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08), which carries only the negative-direction TOR signalling term (GO:0032007); the positive-direction claim cannot be traced back to donor evidence. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPK inhibits mTORC1 via phosphorylation of TSC2 and Raptor |
| GO:0061462 protein localization to lysosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ortholog transfer from human PRKAA2, reflecting the lysosome-centered nutrient-sensing pathway in which AMPK is recruited to lysosomal membranes via the AXIN-LKB1 scaffold during glucose starvation and controls downstream mTORC1 signaling. Real biology, but a context-specific spatial-regulatory aspect rather than a core function. Reason: The lysosomal AMPK pool is well documented in mammalian cells and consistent with the GOA acts_upstream_of_or_within qualifier, but it describes where/how AMPK is regulated during glucose starvation, not a primary output of the kinase; kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); lysosomal AXIN-LKB1 recruitment is well described for mammalian AMPK but describes where the kinase is regulated, not a kinase output. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research.md AMPK is recruited to **lysosomal membranes** during glucose starvation, where a scaffold (AXIN-LKB1) facilitates AMPKΞ±2 phosphorylation and activation |
| GO:0085020 protein K6-linked ubiquitination | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Ortholog transfer from human PRKAA2. AMPK is a protein kinase with no ubiquitin-ligase activity; any connection to K6-linked ubiquitination is at most an upstream regulatory effect on a specific substrate in the human source context (the GOA qualifier is acts_upstream_of_or_within). Such a narrowly specific ubiquitination-linkage term attached to a kinase over-states its role in the process. Reason: The gene-level claim conflates a downstream consequence of AMPK phosphorylation with participation in ubiquitin transfer itself; no support for this process appears in the reviewed rat literature or deep-research syntheses (notably, the documented AMPKalpha2-ubiquitin connection runs the other way - AMPKalpha2 suppresses ubiquitination of its partner SCOT). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); the donor is a kinase with no ubiquitin-transfer activity, so the direct process term misattributes a downstream consequence. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPKΞ±2 binds and stabilizes SCOT |
| GO:1904263 positive regulation of TORC1 signaling | ISO GO_REF:0000121 | REMOVE | Summary: Direction contradicts AMPK's canonical and well-established role - AMPKΞ±2 is a negative regulator of mTORC1 (via TSC2/Raptor phosphorylation), not a positive regulator. This ortholog-transferred annotation attributes the opposite regulatory direction and is factually incorrect, not merely imprecise, so it should be removed. Propagation Review Root cause: SOURCE BAD Failure modes: REGULATORY SIGN INVERSION Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE BAD The human donor record carries negative regulation of TOR signaling (GO:0032007) and no positive-direction TORC1 term at all (QuickGO, checked 2026-08); the transferred assertion inverts the donor's established regulatory sign. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPK inhibits mTORC1 via phosphorylation of TSC2 and Raptor |
| GO:0004674 protein serine/threonine kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO annotation consistent with curated evidence for this term. |
| GO:0140823 histone H2BS36 kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO annotation consistent with curated evidence for this term. |
| GO:1905691 lipid droplet disassembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:1990044 protein localization to lipid droplet | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged sequence-similarity transfer from human PRKAA2 (UniProtKB:P54646). AMPK's involvement in directing proteins to lipid droplets is a contextual output of its lipid-metabolic signaling, in line with the non-core lipid droplet disassembly ISO row. Reason: Defensible transferred biology, but a downstream, context-dependent role rather than the core energy-sensing kinase function; kept as non-core consistent with the IBA and ISO rows for this term. |
| GO:1990044 protein localization to lipid droplet | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO transfer (mouse Prkaa2 and human PRKAA2 sources) of the same lipid-droplet protein-targeting role reviewed under the IBA and ISS rows. Contextual output of AMPK lipid-metabolic signaling, not a core function. Reason: Consistent with the IBA/ISS rows for this term and the non-core lipid droplet disassembly annotation; downstream and context-dependent. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SUPPORTS TRANSFER Human PRKAA2 carries this term with direct evidence (IDA, PMID:34077757); real donor biology, but a downstream, context-dependent output. MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS TRANSFER Mouse Prkaa2 carries the same term (IDA, PMID:34077757), consistent with the IBA and ISS rows reviewed elsewhere in this file. |
| GO:0006646 phosphatidylethanolamine biosynthetic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Ortholog transfer from human PRKAA2. AMPK phosphorylates and regulates phospholipid-biosynthetic enzymes as part of its general suppression of anabolic lipid metabolism; it does not itself carry out phosphatidylethanolamine synthesis. Annotating the upstream kinase to the direct biosynthetic process term mirrors the fatty acid/cholesterol biosynthetic process rows already judged inappropriate in this review. Reason: The GOA acts_upstream_of_or_within qualifier acknowledges the indirect role, but as a gene-function statement the direct biosynthetic term over-annotates a (likely negative) regulatory input; treated consistently with the removed fatty acid/sterol biosynthetic process rows, retained here as over-annotation because the ISO qualifier is explicit. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); the donor's lipid annotations are regulatory (e.g. GO:0008610 by ISS), so a direct phospholipid-biosynthesis term over-reads them. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md Functionally, AMPKΞ±2 integrates energy stress to inhibit anabolic metabolism and promote catabolism and autophagy |
| GO:0006656 phosphatidylcholine biosynthetic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Ortholog transfer from human PRKAA2. As for the phosphatidylethanolamine row, AMPK acts as an upstream (largely inhibitory) regulator of phospholipid-biosynthetic enzymes within its general suppression of anabolic lipid metabolism; it is not part of the phosphatidylcholine biosynthesis pathway itself. Reason: Same judgment as GO:0006646 - the direct biosynthetic process term over-annotates an indirect regulatory input already acknowledged by the acts_upstream_of_or_within qualifier; consistent with the removed fatty acid/sterol biosynthetic process rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); as for the phosphatidylethanolamine row, the donor evidence is regulatory rather than participation in phospholipid synthesis. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md Functionally, AMPKΞ±2 integrates energy stress to inhibit anabolic metabolism and promote catabolism and autophagy |
| GO:0090200 positive regulation of release of cytochrome c from mitochondria | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ortholog transfer from human PRKAA2. Sustained or severe AMPK activation can be pro-apoptotic in specific settings (e.g. prolonged metabolic stress in hepatocytes), engaging the mitochondrial pathway, while mild activation is cytoprotective. A context-dependent, pleiotropic outcome, not a core AMPK function. Reason: Kept as non-core alongside the hepatocyte apoptosis rows and the already-reviewed negative regulation of apoptotic process ISO row - AMPK influences apoptosis bidirectionally depending on stress intensity and context; the GOA acts_upstream_of_or_within qualifier reflects this indirect role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); pro-apoptotic effects of sustained AMPK activation are context-dependent, so the transferred claim stays non-core. |
| GO:0097284 hepatocyte apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ortholog transfer from human PRKAA2 with an acts_upstream_of_or_within qualifier. AMPK modulates hepatocyte survival decisions during metabolic stress (both promoting and restraining apoptosis depending on context - the companion negative-regulation row is annotated from the same source). A tissue-specific, context-dependent role, not core. Reason: Real but pleiotropic liver-context biology downstream of the core energy-sensing function; kept as non-core together with the cytochrome c release and negative regulation of hepatocyte apoptosis rows. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SOURCE STALE OR MISSING Not present on the current human PRKAA2 record (QuickGO, checked 2026-08); a liver-context survival phenotype rather than an output of the kinase. |
| GO:1903944 negative regulation of hepatocyte apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ortholog transfer from human PRKAA2. Consistent with AMPK's cytoprotective role under mild energy stress - AMPK activation protects hepatocytes against apoptosis in several liver-injury models - and with the already-reviewed negative regulation of apoptotic process ISO row. Tissue-specific and context-dependent, so non-core. Reason: Defensible transferred biology reflecting AMPK's pro-survival arm in liver, but a contextual outcome of the core energy-sensing function; kept as non-core with the other apoptosis-related rows. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P54646 Β· human PRKAA2 SUPPORTS TRANSFER Human PRKAA2 carries this term with direct evidence (IDA, PMID:32029622), but it is a tissue-specific, context-dependent outcome of the core energy-sensing function. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Ortholog-based annotation from mouse-rat comparisons. Cytoplasmic localization is conserved across mammalian AMPK Ξ±2 subunits for metabolic regulatory functions. Reason: Strong orthology evidence supports cytoplasmic localization, consistent with other annotation types and functional requirements. |
| GO:0062028 regulation of stress granule assembly | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Likely over-annotation; term is too broad for PRKAA2. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS SOURCE BUT NOT TARGET Mouse Prkaa2 carries the term via IGI (PMID:27430620); the donor evidence bears on granule assembly in one stress context rather than establishing a general regulatory role for the rat gene. |
| GO:0010494 cytoplasmic stress granule | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO transfer from mouse Prkaa2. Recruitment of AMPK to cytoplasmic stress granules has been reported in mammalian cells and fits its broader stress-responsive redistribution, but it is a stress-condition-specific localization, not a core site of function. Reason: Kept as non-core - a factual, condition-dependent localization observation. The related process term regulation of stress granule assembly was marked over-annotated in this review because a regulatory role is less established than mere presence in granules; the divergence between the two rows is deliberate (component observed vs regulatory claim). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS TRANSFER Mouse Prkaa2 has a direct IDA for stress-granule localisation (PMID:27430620); a stress-condition-specific redistribution, so non-core. |
| GO:0010629 negative regulation of gene expression | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0030424 axon | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO transfer from mouse Prkaa2, corroborated by direct rat IMP evidence (PMID:25788287) for AMPK activity in axons of primary hippocampal neurons. Real but neuron-context localization; non-core. Reason: Consistent with the IMP and IEA rows for this term; axonal localization is a cell-type-specific distribution of the broadly expressed kinase. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS TRANSFER Mouse Prkaa2 carries the axon annotation (IGI, PMID:25788287) from the same study that provides the rat IMP evidence; neuron-context localisation. |
| GO:0030424 axon | IMP PMID:25788287 Polarized activities of AMPK and BRSK in primary hippocampal... | KEEP AS NON CORE | Summary: Direct experimental evidence in rat primary hippocampal neurons - FRET-based reporter imaging showed stimulated AMPK activity throughout the neuron with maximal activity in the distal axon (PMID:25788287, full text available). Solid localization evidence, but a neuron-specific context rather than a core functional site. Reason: The experiment (rat neurons, Ca2+ and 2-DG stimulation of an AMPK/BRSK activity reporter) genuinely places active AMPK in axons; kept as non-core because neuronal compartment localization is cell-type-specific and peripheral to the core energy-sensing function. Supporting Evidence: PMID:25788287 AMPK activity is stimulated by either Ca(2+) or 2-DG in the soma, dendrites, and axons of hippocampal neurons, with maximal stimulated activity observed in the distal region of the axon |
| GO:0030425 dendrite | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO transfer from mouse Prkaa2, corroborated by direct rat IMP evidence (PMID:25788287) for AMPK activity in dendrites of primary hippocampal neurons. Real but neuron-context localization; non-core. Reason: Consistent with the IMP and IEA rows for this term; dendritic localization is a cell-type-specific distribution of the broadly expressed kinase. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS TRANSFER Mouse Prkaa2 carries the dendrite annotation (IGI, PMID:25788287) from the same study that provides the rat IMP evidence; neuron-context localisation. |
| GO:0030425 dendrite | IMP PMID:25788287 Polarized activities of AMPK and BRSK in primary hippocampal... | KEEP AS NON CORE | Summary: Direct experimental evidence in rat primary hippocampal neurons - FRET reporter imaging showed Ca2+/2-DG-stimulated AMPK activity in dendrites (PMID:25788287, full text available). Solid localization evidence in a neuron-specific context; non-core. Reason: Same study and judgment as the axon IMP row - genuine rat evidence for dendritic AMPK activity, kept as non-core because neuronal compartment localization is cell-type-specific and peripheral to the core energy-sensing function. Supporting Evidence: PMID:25788287 AMPK activity is stimulated by either Ca(2+) or 2-DG in the soma, dendrites, and axons of hippocampal neurons, with maximal stimulated activity observed in the distal region of the axon |
| GO:0034599 cellular response to oxidative stress | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0043025 neuronal cell body | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO transfer from mouse Prkaa2, corroborated by direct rat IMP evidence (PMID:25788287) for AMPK activity in the soma of primary hippocampal neurons. Real but neuron-context localization; non-core. Reason: Consistent with the IMP and IEA rows for this term; somatic localization in neurons is a cell-type-specific distribution of the broadly expressed kinase. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS TRANSFER Mouse Prkaa2 carries the neuronal cell body annotation (IGI, PMID:25788287) from the same study that provides the rat IMP evidence; neuron-context localisation. |
| GO:0043025 neuronal cell body | IMP PMID:25788287 Polarized activities of AMPK and BRSK in primary hippocampal... | KEEP AS NON CORE | Summary: Direct experimental evidence in rat primary hippocampal neurons - FRET reporter imaging showed Ca2+/2-DG-stimulated AMPK activity in the soma (PMID:25788287, full text available). Solid localization evidence in a neuron-specific context; non-core. Reason: Same study and judgment as the axon and dendrite IMP rows - genuine rat evidence for somatic AMPK activity, kept as non-core because neuronal compartment localization is cell-type-specific and peripheral to the core energy-sensing function. Supporting Evidence: PMID:25788287 AMPK activity is stimulated by either Ca(2+) or 2-DG in the soma, dendrites, and axons of hippocampal neurons, with maximal stimulated activity observed in the distal region of the axon |
| GO:0070507 regulation of microtubule cytoskeleton organization | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Likely over-annotation; term is too broad for PRKAA2. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS SOURCE BUT NOT TARGET Mouse donor support is an IGI (PMID:27430620); it does not establish the broad microtubule-cytoskeleton regulatory role the term asserts for the rat gene. |
| GO:0071277 cellular response to calcium ion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0071333 cellular response to glucose stimulus | ISO GO_REF:0000121 | ACCEPT | Summary: ISO annotation consistent with curated evidence for this term. |
| GO:1903829 positive regulation of protein localization | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: RGD ISO transfer from mouse Prkaa2. AMPK phosphorylation does redirect the localization of specific substrates (e.g. nuclear translocation of transcription regulators), but this grouping term is so broad that it conveys essentially no information about which protein is localized where. Uninformative at the gene level. Reason: Parent-level regulation term that is true only via specific, already-better-annotated events; matches this review's treatment of other overly broad regulation terms (e.g. regulation of microtubule cytoskeleton organization). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS SOURCE BUT NOT TARGET The mouse donor IGI (PMID:27430620) concerns relocalisation of particular AMPK substrates; the grouping term conveys nothing about which protein is localised where. |
| GO:0010468 regulation of gene expression | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0014850 response to muscle activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0071466 cellular response to xenobiotic stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0016241 regulation of macroautophagy | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0071380 cellular response to prostaglandin E stimulus | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Likely over-annotation; term is too broad for PRKAA2. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS SOURCE BUT NOT TARGET The mouse donor IGI (PMID:23479225) is a narrow prostaglandin-E stimulus context, too fine-grained to carry as a rat gene-level annotation. |
| GO:0004712 protein serine/threonine/tyrosine kinase activity | ISO GO_REF:0000121 | REMOVE | Summary: Annotation is overly general or unsupported in this context and should be removed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P54646 Β· human PRKAA2 SUPPORTS SOURCE BUT NOT TARGET Human PRKAA2 carries the term by IDA (PMID:22797923), but rat AMPKalpha2 is a serine/threonine kinase and the combined Ser/Thr/Tyr term overstates its specificity. |
| GO:0003682 chromatin binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0008610 lipid biosynthetic process | ISO GO_REF:0000121 | REMOVE | Summary: AMPK does not execute a function within lipid biosynthesis - it phosphorylates and inactivates lipogenic enzymes, i.e. negatively regulates the process. The donor annotations are experimentally grounded (mouse IDA, PMID:21459323; human ISS/IEA), so the defect is the term's regulatory-sign and role conflation rather than an absent source; the biology is captured by the negative-regulation rows. Removed, consistent with the parallel ISS row for the same term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1336173 Β· mouse Prkaa2 SUPPORTS SOURCE BUT NOT TARGET Mouse Prkaa2 has an IDA for this term (PMID:21459323), but AMPK regulates (largely inhibits) lipid biosynthesis rather than participating in it. |
| GO:0010508 positive regulation of autophagy | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0032007 negative regulation of TOR signaling | ISO GO_REF:0000121 | ACCEPT | Summary: ISO annotation consistent with curated evidence for this term. |
| GO:0042752 regulation of circadian rhythm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Evidence supports the term but it is not core to PRKAA2 function. |
| GO:0042593 glucose homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: ISO annotation consistent with curated evidence for this term. |
| GO:0005737 cytoplasm | IDA PMID:18256313 Control of glycogen synthase through ADIPOR1-AMPK pathway in... | ACCEPT | Summary: Direct experimental evidence from PMID:18256313 showing AMPK localization in renal epithelial cells. Cytoplasmic localization is essential for AMPK's role in controlling glycogen synthase and other metabolic targets in response to energy stress. Reason: Strong experimental evidence for cytoplasmic localization where AMPK performs its primary metabolic regulatory functions. Supporting Evidence: PMID:18256313 Control of glycogen synthase through ADIPOR1-AMPK pathway in renal distal tubules of normal and diabetic rats. |
| GO:0016324 apical plasma membrane | IDA PMID:18256313 Control of glycogen synthase through ADIPOR1-AMPK pathway in... | KEEP AS NON CORE | Summary: Direct immunohistochemical evidence in rat kidney - AMPK alpha1/alpha2 catalytic subunits were detected in the same distal tubule/thick ascending limb cells where ADIPOR1 marks the luminal (apical) membrane (PMID:18256313; abstract-only in cache, curator read the full text). A genuine but tissue-specific membrane-proximal localization supporting luminal adiponectin-AMPK signaling, not a core localization. Reason: Deferring to the UniProt curator on the apical-membrane assignment (the cached abstract confirms the luminal ADIPOR1-AMPK co-localization context but full text is unavailable). Kept as non-core because apical-membrane recruitment in renal epithelium is a specialized, polarized-cell context, in contrast to the core cytoplasmic/nuclear localizations. Supporting Evidence: PMID:18256313 Immunohistochemistry revealed the presence of ADIPOR1 on the luminal portion of distal tubules and thick ascending limb cells. Catalytic subunits alpha(1) and alpha(2), their phosphorylated active forms, and the glycogen-binding subunit beta(2) were also found in the same cells file:rat/Prkaa2/Prkaa2-deep-research.md and at the **apical plasma membrane** in polarized cells |
| GO:0032991 protein-containing complex | IDA PMID:14511394 Complexes between the LKB1 tumor suppressor, STRAD alpha/bet... | MODIFY | Summary: The experiment is sound - native AMPK purified from rat liver (the physiological heterotrimer, activated by the LKB1-STRAD-MO25 upstream kinase complexes characterized in PMID:14511394, full text available) - but the root term protein-containing complex conveys no information. The specific complex AMPKalpha2 belongs to is the nucleotide-activated protein kinase complex (GO:0031588), which already carries rat IDA evidence (PMID:16648175). Reason: Root CC term is uninformative for a protein whose complex identity is precisely known; the essence (complex membership demonstrated experimentally in rat) is correct, so replace with the specific heterotrimer term rather than removing the experimental annotation. Proposed replacements: nucleotide-activated protein kinase complex Supporting Evidence: PMID:14511394 AMPK was purified from rat liver as described previously PMID:16648175 AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic alpha-subunits and regulatory beta- and gamma-subunits with multiple isoforms |
| GO:0031588 nucleotide-activated protein kinase complex | IDA PMID:16648175 Activation of AMPK alpha- and gamma-isoform complexes in the... | ACCEPT | Summary: Direct rat experimental evidence - in intact rat heart, the alpha2 catalytic isoform co-immunoprecipitated with regulatory gamma1/gamma2 isoforms and its complex-associated kinase activity was stimulated by ischemia (PMID:16648175; abstract-only in cache but the abstract itself documents the co-immunoprecipitation). This is the defining evidence that rat AMPKalpha2 is the catalytic subunit of the heterotrimeric AMPK complex. Core. Supporting Evidence: PMID:16648175 The gamma(1)- and gamma(2)-isoforms coimmunoprecipitated with alpha(1)- and alpha(2)-isoforms in proportion to alpha-subunit content |
| GO:0005654 nucleoplasm | TAS Reactome:R-RNO-164087 | ACCEPT | Summary: Reactome-derived localization - the curated rat event "Phosphorylation of rChREBP(Ser 568) by rAMPK" takes place in the nucleus, placing the AMPK heterotrimer in the nucleoplasm. Consistent with AMPKalpha2's nuclear localization signal, nuclear shuttling, and nuclear substrates (ChREBP, histone H2B). Reason: Consistent with the accepted nucleus IEA/ISO and nucleoplasm ISO rows; nuclear-compartment activity on ChREBP is part of the core transcriptional arm of AMPKalpha2 function. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPKΞ±2 contains a nuclear localization signal and can shuttle to the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-RNO-164106 | ACCEPT | Summary: Reactome-derived localization - the curated rat event "rLkb-1 (Stk-11) activates AMPK by phosphorylation" is placed in the nucleus, locating the AMPK heterotrimer in the nucleoplasm during LKB1-mediated Thr172 activation. Consistent with AMPKalpha2 nuclear shuttling and the other accepted nucleus/nucleoplasm rows. Reason: Same judgment as the companion Reactome nucleoplasm row; nuclear localization of AMPKalpha2 is well supported and underlies its chromatin/transcriptional functions. Supporting Evidence: file:rat/Prkaa2/Prkaa2-deep-research-falcon.md AMPKΞ±2 contains a nuclear localization signal and can shuttle to the nucleus |
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Download this section (compressed HTML)Q: How do the Ξ±1 and Ξ±2 subunits of AMPK differ in their tissue distribution, regulation, and substrate specificity?
Q: What determines the subcellular localization of PRKAA2-containing AMPK complexes and how does this affect their function?
Q: How does PRKAA2 contribute to metabolic sensing and energy homeostasis in different physiological conditions?
Q: What role does PRKAA2 play in cellular stress responses beyond its canonical metabolic functions?
Q: Does AMPKΞ±2's binding and stabilization of SCOT (succinyl-CoA:3-ketoacid CoA transferase) in skeletal muscle ketone utilization represent a broader non-catalytic scaffolding function, and can this stabilization mechanism be confirmed in rat tissues?
Experiment: Proteomics analysis to identify PRKAA2-specific substrates and interacting partners compared to PRKAA1
Experiment: Live-cell imaging using FRET-based biosensors to monitor PRKAA2-containing AMPK activity in real-time
Experiment: Metabolomics analysis of tissues from PRKAA2 knockout mice to understand metabolic pathway alterations
Experiment: Single-cell analysis of AMPK activity and metabolic state in different cell types using genetically encoded indicators
Experiment: Co-immunoprecipitation and cycloheximide-chase protein stability assays in rat skeletal muscle to test whether AMPKΞ±2 binds and stabilizes SCOT (succinyl-CoA:3-ketoacid CoA transferase) and limits its ubiquitin/proteasome-mediated degradation, probing a non-catalytic scaffolding role in ketone utilization
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Download this section (compressed HTML)π View Pathway Visualization Interactive pathway diagram with detailed annotations