PKM (Pyruvate Kinase M) encodes pyruvate kinase isoforms that catalyze the final step of glycolysis: conversion of phosphoenolpyruvate and ADP to pyruvate and ATP. CRITICAL ISOFORM BIOLOGY: Alternative splicing of mutually exclusive exons 9/10 produces isoforms with FUNDAMENTALLY DIFFERENT metabolic properties: (1) PKM1 (P14618-2, M1-PK) is expressed in ADULT differentiated tissues (muscle, brain, heart). It is a constitutively active homotetramer with HIGH pyruvate kinase activity, supporting efficient ATP generation via complete glycolysis and oxidative metabolism. (2) PKM2 (P14618-1, M2-PK) is expressed in EMBRYONIC tissues, PROLIFERATING cells, and nearly all CANCERS. It has LOW basal activity and is allosterically regulated by fructose-1,6-bisphosphate (FBP). PKM2 can exist as inactive monomer/dimer or active tetramer. LOW activity allows glycolytic intermediates to accumulate for biosynthetic pathways (nucleotides, amino acids, lipids) - the metabolic basis of the WARBURG EFFECT in cancer. PKM2-SPECIFIC FUNCTIONS (not shared by PKM1): - Nuclear translocation and transcription coactivator activity (with HIF-1alpha, beta-catenin, STAT3, and Oct-4) - Reported non-canonical protein kinase activity (towards histone H3 Thr11 and STAT3 Tyr705), though direct PEP/ATP-dependent protein phosphorylation by PKM2 has been biochemically disputed (PMID:26300261) - These non-glycolytic nuclear functions contribute to cancer cell proliferation. The PKM1-to-PKM2 switch is controlled by hnRNP splicing factors (hnRNPA1, hnRNPA2, PTBP1) and is a metabolic hallmark distinguishing differentiated vs proliferating cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004743 pyruvate kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Both PKM1 and PKM2 isoforms possess pyruvate kinase activity, catalyzing the final step of glycolysis (PEP + ADP -> pyruvate + ATP). However, these isoforms have FUNDAMENTALLY DIFFERENT enzymatic properties. PKM1 (P14618-2) is constitutively active with HIGH activity [PMID:20847263]. PKM2 (P14618-1) has LOW basal activity and requires allosteric activation by fructose-1,6-bisphosphate (FBP) to form active tetramers [PMID:15996096, PMID:18337815]. The IBA annotation is correct but does not capture this critical isoform-specific difference in activity levels. Reason: Core function for both isoforms. Pyruvate kinase activity is the canonical function of PKM. Both isoforms catalyze this reaction, though with vastly different kinetic properties and regulation. Supporting Evidence: PMID:20847263 Paradoxically, decreased pyruvate kinase enzyme activity accompanies the expression of PKM2 in rapidly dividing cancer cells and tissues. file:human/PKM/PKM-deep-research-falcon.md PKM catalyzes the terminal glycolytic step: **PEP + ADP β pyruvate + ATP**. This reaction couples high-energy phosphate transfer to ATP production and is a principal flux-control point in glycolysis. file:human/PKM/PKM-deep-research-affinage.md The interconversion between oligomeric states is the central regulatory switch: tetramerization favors enzymatic pyruvate kinase activity, whereas dimer/monomer formation favors nuclear functions |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Both PKM1 and PKM2 localize to the cytoplasm where they perform their glycolytic function. PKM1 is exclusively cytoplasmic [UniProt P14618]. PKM2 is predominantly cytoplasmic but can translocate to the nucleus upon specific stimuli such as EGFR activation [PMID:22056988, PMID:17308100]. Reason: Cytoplasmic localization is correct for both isoforms and represents the primary site of glycolytic function. Supporting Evidence: PMID:22056988 EGF treatment resulted in the nuclear accumulation of PKM2 in U87/EGFR human glioblastoma (GBM) cells... In addition, PKM1 failed to translocate into the nucleus upon EGF stimulation |
| GO:0006096 glycolytic process | IBA GO_REF:0000033 | ACCEPT | Summary: Both isoforms participate in glycolysis. PKM1 supports efficient glycolysis for ATP production. PKM2's low activity in cancer cells diverts glycolytic intermediates to biosynthetic pathways (the Warburg effect) [PMID:20847263]. Reason: Core function for both isoforms. Both participate in glycolysis though PKM2's low activity fundamentally alters glycolytic flux in proliferating cells. Supporting Evidence: PMID:20847263 The M2 isoform of pyruvate kinase (PKM2) promotes the metabolism of glucose by aerobic glycolysis and contributes to anabolic metabolism. |
| GO:0032869 cellular response to insulin stimulus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetically projected involvement in the cellular insulin response from PANTHER node PTN000212861 (rat Pklr donor RGD:3336), reflecting hormonal regulation of the hepatic pyruvate kinase paralog rather than PKM's own molecular function. Reason: This IBA is projected from PANTHER family node PTN000212861 (rat liver/RBC pyruvate kinase Pklr, RGD:3336). While insulin/glucagon signaling regulates hepatic Pklr transcription and phosphorylation upstream, this describes upstream hormonal modulation of a paralogous enzyme rather than a signaling step PKM itself performs. This represents a regulatory response rather than a core biochemical function. Harmonized with human PKLR (MARK_AS_OVER_ANNOTATED on the same PTN000212861 node). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION CONTEXT OR TISSUE MISMATCH Sources checked: RGD:3336 Β· Pklr (rat) SUPPORTS SOURCE BUT NOT TARGET Rat hepatic/RBC paralog (Pklr); captures upstream hormonal regulation of the liver enzyme rather than a molecular process PKM itself performs. PANTHER:PTN000212861 Β· pyruvate kinase family node SUPPORTS SOURCE BUT NOT TARGET Family-node projection of an upstream hepatic regulatory biological process from rat Pklr (RGD:3336) that does not represent a direct signaling role of PKM. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: PKM binds ADP as a substrate for the pyruvate kinase reaction. This is a correct but overly general annotation - the more specific pyruvate kinase activity annotation is more informative. Reason: Correct parent term of ATP binding, which is required for pyruvate kinase activity. Both isoforms bind nucleotides. |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Pyruvate kinase requires Mg2+ as a cofactor [UniProt P14618]. This applies to both isoforms. Reason: Mg2+ is an essential cofactor for pyruvate kinase activity. Both isoforms require this ion. |
| GO:0003824 catalytic activity | IEA GO_REF:0000120 | ACCEPT | Summary: PKM has catalytic activity. This is an overly broad parent term - the specific pyruvate kinase activity annotation is more informative. Reason: True but uninformative parent term. Both isoforms have catalytic activity. |
| GO:0004674 protein serine/threonine kinase activity | IEA P14618-1 GO_REF:0000003 | MARK AS OVER ANNOTATED | Summary: Electronic EC2GO mapping (EC 2.7.11.1) from UniProt's Isoform M2 (PKM2, P14618-1) catalytic activity annotation for histone H3 Thr-11 phosphorylation [PMID:22901803]. Direct PKM2 protein-kinase activity is biochemically disputed [PMID:26300261] and absent in PKM1. Reason: This IEA row derives from EC 2.7.11.1 on Isoform M2 (P14618-1) in UniProt (based on reported H3T11 phosphorylation, PMID:22901803; the UniProt CC:FUNCTION snippet below is cited as provenance of the EC2GO mapping), dropped to the canonical gene level in GOA. Biochemical reconstitution using [32P]-PEP and PKM2-null systems failed to detect any direct PKM2-dependent protein kinase activity using either PEP or ATP as a phosphate donor (Hosios et al. 2015, PMID:26300261). Because UniProt retains the Isoform M2 catalytic activity entry with ECO:0000269 evidence (including post-2015 citations), this remains a live dispute (finding_status: DISPUTED) and is marked MARK_AS_OVER_ANNOTATED rather than REMOVE. Supporting Evidence: file:human/PKM/PKM-uniprot.txt Translocates into the nucleus in response to various signals, such as EGF receptor activation, and homodimerizes, leading to its conversion into a protein threonine- and tyrosine-protein kinase PMID:26300261 We investigated the protein kinase activity of PKM2; however, we were unable to demonstrate PKM2-dependent phosphorylation of any proteins in vitro using either PEP or ATP as a phosphate donor. Instead, all PKM2-dependent phosphotransfer events observed involved regeneration of ATP from ADP and PEP, the known function of PKM2 in glycolysis. |
| GO:0004713 protein tyrosine kinase activity | IEA P14618-1 GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: Electronic Rhea2GO mapping (RHEA:10596) from UniProt's Isoform M2 (PKM2, P14618-1) catalytic activity annotation for STAT3 Tyr-705 phosphorylation [PMID:22306293]. Direct PKM2 protein-kinase activity is biochemically disputed [PMID:26300261] and absent in PKM1. Reason: This IEA row derives from RHEA:10596 (EC 2.7.10.2) on Isoform M2 (P14618-1) in UniProt (based on reported STAT3 Tyr-705 phosphorylation, PMID:22306293; the UniProt CC:FUNCTION snippet below is cited as provenance of the Rhea2GO mapping), dropped to the canonical gene level in GOA. Biochemical reconstitution using [32P]-PEP and PKM2-null systems failed to detect any direct PKM2-dependent protein kinase activity using either PEP or ATP as a phosphate donor (Hosios et al. 2015, PMID:26300261). Because UniProt retains the Isoform M2 catalytic activity entry with ECO:0000269 evidence, this remains a live dispute (finding_status: DISPUTED) and is marked MARK_AS_OVER_ANNOTATED rather than REMOVE. Supporting Evidence: file:human/PKM/PKM-uniprot.txt Translocates into the nucleus in response to various signals, such as EGF receptor activation, and homodimerizes, leading to its conversion into a protein threonine- and tyrosine-protein kinase PMID:26300261 We investigated the protein kinase activity of PKM2; however, we were unable to demonstrate PKM2-dependent phosphorylation of any proteins in vitro using either PEP or ATP as a phosphate donor. Instead, all PKM2-dependent phosphotransfer events observed involved regeneration of ATP from ADP and PEP, the known function of PKM2 in glycolysis. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IEA P14618-1 GO_REF:0000003 | MARK AS OVER ANNOTATED | Summary: Electronic EC2GO mapping (EC 2.7.10.2) from UniProt's Isoform M2 (PKM2, P14618-1) catalytic activity annotation. Direct PKM2 protein-kinase activity is biochemically disputed [PMID:26300261] and absent in PKM1. Reason: This IEA row derives from EC 2.7.10.2 on Isoform M2 (P14618-1) in UniProt (the UniProt CC:FUNCTION snippet below is cited as provenance of the EC2GO mapping), dropped to the canonical gene level in GOA. Biochemical reconstitution using [32P]-PEP and PKM2-null systems failed to detect any direct PKM2-dependent protein kinase activity using either PEP or ATP as a phosphate donor (Hosios et al. 2015, PMID:26300261). Because UniProt retains the Isoform M2 catalytic activity entry with ECO:0000269 evidence, this remains a live dispute (finding_status: DISPUTED) and is marked MARK_AS_OVER_ANNOTATED rather than REMOVE. Supporting Evidence: file:human/PKM/PKM-uniprot.txt Translocates into the nucleus in response to various signals, such as EGF receptor activation, and homodimerizes, leading to its conversion into a protein threonine- and tyrosine-protein kinase PMID:26300261 We investigated the protein kinase activity of PKM2; however, we were unable to demonstrate PKM2-dependent phosphorylation of any proteins in vitro using either PEP or ATP as a phosphate donor. Instead, all PKM2-dependent phosphotransfer events observed involved regeneration of ATP from ADP and PEP, the known function of PKM2 in glycolysis. |
| GO:0004743 pyruvate kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation. Both isoforms have pyruvate kinase activity, though with vastly different kinetic properties. Reason: Core function for both isoforms. This IEA annotation is redundant with the IBA annotation but not incorrect. |
| GO:0005524 ATP binding | IEA GO_REF:0000043 | ACCEPT | Summary: PKM binds ATP/ADP as substrates for pyruvate kinase reaction. Both isoforms bind ATP. Reason: Correct annotation for both isoforms as ATP/ADP binding is essential for pyruvate kinase activity. |
| GO:0005634 nucleus | IEA P14618-1 GO_REF:0000044 | KEEP AS NON CORE | Summary: PKM2 (NOT PKM1) translocates to the nucleus upon EGFR activation and other stimuli [PMID:22056988, PMID:17308100]. PKM1 does NOT translocate to the nucleus. This is a PKM2-SPECIFIC localization. Reason: Stimulus-dependent nuclear translocation applies specifically to the PKM2 isoform (P14618-1) during non-canonical transcriptional and signaling roles, whereas canonical glycolytic catalysis occurs in the cytosol. PMID:22056988 demonstrates that PKM1 fails to translocate into the nucleus upon EGF stimulation. Supporting Evidence: PMID:22056988 In addition, PKM1 failed to translocate into the nucleus upon EGF stimulation |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Both PKM1 and PKM2 localize to the cytoplasm. This is the primary site of glycolytic function. Reason: Correct for both isoforms. Cytoplasmic localization is the primary location for glycolytic function. |
| GO:0006096 glycolytic process | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation. Both isoforms participate in glycolysis. Reason: Core function for both isoforms. Redundant with IBA annotation but not incorrect. |
| GO:0006417 regulation of translation | IEA P14618-1 GO_REF:0000043 | KEEP AS NON CORE | Summary: PKM2 may act as a translation regulator for a subset of mRNAs, associating with ER-bound ribosomes and promoting translation of ER-destined mRNAs [UniProt, by similarity]. This function is attributed to PKM2 specifically. Reason: This is a non-canonical moonlighting function of PKM2 based on similarity evidence. Not a core function. |
| GO:0016301 kinase activity | IEA GO_REF:0000043 | ACCEPT | Summary: PKM has kinase activity - pyruvate kinase activity for both isoforms, and protein kinase activity for PKM2 only. This is a broad parent term. Reason: True but uninformative parent term encompassing both pyruvate kinase and protein kinase activities. |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: PKM has transferase activity (phosphotransferase). This is a very broad parent term. Reason: True but uninformative high-level parent term. Both isoforms have transferase activity. |
| GO:0030955 potassium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Pyruvate kinase requires K+ as a cofactor [UniProt P14618]. This applies to both isoforms. Reason: K+ is an essential cofactor for pyruvate kinase activity. Both isoforms require this ion. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: PKM binds metal ions (Mg2+, K+) as cofactors. Parent term of magnesium and potassium binding. Reason: True parent term. Both isoforms bind metal ion cofactors. |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | REMOVE | Summary: Yeast two-hybrid study identifying RAF kinase protein-protein interactions. PKM was identified as an interactor. This is a generic protein binding annotation from high-throughput screening. Reason: Bare GO:0005515 protein binding from a yeast two-hybrid screen is uninformative under the protein-binding policy and provides no specific molecular function. Supporting Evidence: PMID:12620389 Novel raf kinase protein-protein interactions found by an exhaustive yeast two-hybrid analysis. |
| GO:0005515 protein binding | IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu... | REMOVE | Summary: PKM identified as a Huntingtin interacting protein and potential modifier of neurodegeneration. High-throughput interactome study. Reason: Bare GO:0005515 protein binding from an interactome screen is uninformative under the protein-binding policy. Supporting Evidence: PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neurodegeneration. |
| GO:0005515 protein binding | IPI PMID:17620599 Functional specialization of beta-arrestin interactions reve... | REMOVE | Summary: PKM identified in beta-arrestin interactome study. High-throughput proteomics. Reason: Bare GO:0005515 protein binding from a high-throughput proteomics screen is uninformative under the protein-binding policy. Supporting Evidence: PMID:17620599 Functional specialization of beta-arrestin interactions revealed by proteomic analysis. |
| GO:0005515 protein binding | IPI PMID:18519040 Isoform-specific interaction of pyruvate kinase with hepatit... | REMOVE | Summary: Isoform-specific interaction of pyruvate kinase with HCV NS5B. The study specifically examines PKM2 interaction with viral protein. Reason: Bare GO:0005515 protein binding is uninformative under the protein-binding policy; this row reflects an exogenous host-pathogen interaction with viral NS5B rather than an endogenous molecular function of PKM. Supporting Evidence: PMID:18519040 Epub 2008 Jun 2. Isoform-specific interaction of pyruvate kinase with hepatitis C virus NS5B. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | REMOVE | Summary: PKM identified in telomere signaling regulator screen. High-throughput study. Reason: Bare GO:0005515 protein binding from a high-throughput complementation screen is uninformative under the protein-binding policy. Supporting Evidence: PMID:21044950 Epub 2010 Nov 2. Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. |
| GO:0005515 protein binding | IPI PMID:21725354 Death-associated protein kinase increases glycolytic rate th... | MODIFY | Summary: Death-associated protein kinase (DAPK) directly binds and functionally activates pyruvate kinase M2 (PKM2), increasing glycolytic rate. Reason: PMID:21725354 demonstrates a direct, functionally characterized physical interaction between PKM and the serine/threonine kinase DAPK that allosterically activates pyruvate kinase activity. Because DAPK is a protein kinase, bare GO:0005515 should be refined to the specific child term GO:0019901 (protein kinase binding). Proposed replacements: protein kinase binding Supporting Evidence: PMID:21725354 Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase. |
| GO:0005515 protein binding | IPI P14618-1 PMID:22056988 Nuclear PKM2 regulates Ξ²-catenin transactivation upon EGFR a... | MODIFY | Summary: PKM2 (specifically) interacts with beta-catenin (CTNNB1) in the nucleus to regulate transcription of CCND1 [PMID:22056988]. This is a PKM2-SPECIFIC interaction that requires c-Src phosphorylation of beta-catenin at Y333. Reason: This is a functionally significant PKM2-specific interaction. The generic protein binding term fails to capture the isoform specificity and functional significance. Should be annotated as beta-catenin binding for PKM2 specifically. Proposed replacements: beta-catenin binding Supporting Evidence: PMID:22056988 EGF stimulation resulted in an interaction between endogenous PKM2 and beta-catenin in the nuclear, but not cytosolic, fraction |
| GO:0005515 protein binding | IPI PMID:22898364 Comparative analysis of virus-host interactomes with a mamma... | REMOVE | Summary: PKM identified in virus-host interactome study using protein complementation assay. High-throughput screening. Reason: Bare GO:0005515 protein binding from a high-throughput viral interactome screen is uninformative under the protein-binding policy. Supporting Evidence: PMID:22898364 Aug 8. Comparative analysis of virus-host interactomes with a mammalian high-throughput protein complementation assay based on Gaussia princeps luciferase. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: PKM identified in neurodegenerative disease protein interactome mapping study. Reason: Bare GO:0005515 protein binding from a high-throughput interactome study is uninformative under the protein-binding policy. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:9990017 Modulation of type M2 pyruvate kinase activity by the human ... | REMOVE | Summary: HPV-16 E7 oncoprotein modulates M2-type pyruvate kinase activity. E7 binding promotes PKM2 homodimerization [UniProt]. Reason: Bare GO:0005515 protein binding is uninformative under the protein-binding policy and reflects an exogenous viral oncoprotein interaction rather than an endogenous molecular function of PKM. Supporting Evidence: PMID:9990017 Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. |
| GO:0003729 mRNA binding | IEA P14618-1 GO_REF:0000107 | KEEP AS NON CORE | Summary: PKM2 may bind mRNAs as part of its moonlighting function in translation regulation [UniProt, by similarity]. Associates with ER-bound ribosomes. Reason: Non-canonical moonlighting function of PKM2 based on similarity evidence. Not a core function. |
| GO:0005791 rough endoplasmic reticulum | IEA P14618-1 GO_REF:0000107 | KEEP AS NON CORE | Summary: PKM2 may associate with rough ER as part of its translation regulation function [UniProt, by similarity]. Reason: Associated with moonlighting function in translation regulation. Not a primary localization. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Both PKM1 and PKM2 are cytosolic enzymes where they perform glycolysis. Reason: Correct localization for both isoforms. Primary site of glycolytic activity. |
| GO:0005929 cilium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PKM localization to cilium based on ortholog evidence. Limited direct evidence. Reason: Ortholog-based evidence for specialized localization. Not a primary site of function. |
| GO:0061621 canonical glycolysis | IEA GO_REF:0000107 | ACCEPT | Summary: Both isoforms participate in canonical glycolysis. PKM catalyzes the final step converting PEP to pyruvate. Reason: Core function for both isoforms. More specific than generic glycolytic process term. |
| GO:2000767 positive regulation of cytoplasmic translation | IEA P14618-1 GO_REF:0000107 | KEEP AS NON CORE | Summary: PKM2 may positively regulate translation of ER-destined mRNAs [UniProt, by similarity]. Moonlighting function. Reason: Non-canonical moonlighting function based on similarity evidence. Not a core function. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct assay evidence for cytosolic localization based on immunofluorescence. Both isoforms are cytosolic. Reason: Validated cytosolic localization. Primary site of glycolytic function for both isoforms. |
| GO:0004743 pyruvate kinase activity | IDA PMID:20847263 Evidence for an alternative glycolytic pathway in rapidly pr... | ACCEPT | Summary: Direct demonstration of pyruvate kinase activity. This study examined both PKM1 and PKM2 and showed that PKM2 has lower activity and contributes to the Warburg effect by allowing glycolytic intermediates to accumulate for biosynthesis. Reason: Core function with direct experimental evidence. Both isoforms have activity but with different kinetic properties. Supporting Evidence: PMID:20847263 Paradoxically, decreased pyruvate kinase enzyme activity accompanies the expression of PKM2 in rapidly dividing cancer cells and tissues. |
| GO:0005654 nucleoplasm | TAS P14618-1 Reactome:R-HSA-9766062 | KEEP AS NON CORE | Summary: Reactome pathway annotation for PKM2 and TGIF2 binding the CDH1 gene promoter in the nucleoplasm. This nuclear localization is specific to the PKM2 isoform (P14618-1). Reason: Stimulus-dependent nucleoplasmic localization applies specifically to the PKM2 isoform (P14618-1) during non-canonical transcriptional coactivation/repression, distinct from the canonical cytosolic glycolytic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9861640 | ACCEPT | Summary: Reactome annotation for CTLH E3 ligase ubiquitinating PKM-1. Cytosolic localization is correct for both isoforms. Reason: Correct localization for both isoforms. |
| GO:0005515 protein binding | IPI PMID:27573352 TSC22D2 interacts with PKM2 and inhibits cell growth in colo... | REMOVE | Summary: TSC22D2 interacts with PKM2 and inhibits cell growth in colorectal cancer. The interaction reduces nuclear PKM2 levels and represses cyclin D1 transcription. Reason: Bare GO:0005515 protein binding is uninformative under the protein-binding policy; no specific binding descendant term applies to TSC22D2 binding. Supporting Evidence: PMID:27573352 TSC22D2 interacts with PKM2 and inhibits cell growth in colorectal cancer. |
| GO:0005634 nucleus | IDA P14618-1 PMID:27573352 TSC22D2 interacts with PKM2 and inhibits cell growth in colo... | KEEP AS NON CORE | Summary: Direct evidence for PKM nuclear localization. The study specifically examines PKM2 (isoform M2) nuclear localization and its regulation by TSC22D2. Reason: Direct experimental evidence for stimulus-dependent, PKM2-specific nuclear localization, distinct from the canonical cytosolic glycolytic localization. Supporting Evidence: PMID:27573352 TSC22D2 interacts with PKM2 and inhibits cell growth in colorectal cancer. |
| GO:0005737 cytoplasm | IDA PMID:27573352 TSC22D2 interacts with PKM2 and inhibits cell growth in colo... | ACCEPT | Summary: Direct evidence for PKM cytoplasmic localization. Both isoforms are cytoplasmic. Reason: Correct for both isoforms. Primary site of glycolytic function. Supporting Evidence: PMID:27573352 TSC22D2 interacts with PKM2 and inhibits cell growth in colorectal cancer. |
| GO:0003729 mRNA binding | ISS P14618-1 GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence similarity-based annotation for mRNA binding. Moonlighting function of PKM2. Reason: Non-canonical function based on similarity. Not a core function. |
| GO:0005791 rough endoplasmic reticulum | ISS P14618-1 GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence similarity-based annotation. Associated with translation regulation moonlighting function. Reason: Non-canonical localization associated with moonlighting function. |
| GO:2000767 positive regulation of cytoplasmic translation | ISS P14618-1 GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence similarity-based annotation for translation regulation. Moonlighting function. Reason: Non-canonical moonlighting function based on sequence similarity. |
| GO:0005515 protein binding | IPI PMID:27199445 JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism... | REMOVE | Summary: JMJD8 interacts with PKM2 and regulates angiogenic sprouting and cellular metabolism. Reason: Bare GO:0005515 protein binding is uninformative under the protein-binding policy; no specific binding descendant term applies to JMJD8 binding. Supporting Evidence: PMID:27199445 JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells. |
| GO:1903672 positive regulation of sprouting angiogenesis | IMP PMID:27199445 JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism... | KEEP AS NON CORE | Summary: PKM regulates angiogenic sprouting through interaction with JMJD8 in endothelial cells. Likely PKM2-mediated based on cancer/proliferation context. Reason: Pleiotropic downstream effect in specialized cell type context. Not a core function of PKM. Supporting Evidence: PMID:27199445 JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells. |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | KEEP AS NON CORE | Summary: High-throughput proteomics study of E-cadherin interactome. PKM identified as an interactor. Reason: High-throughput proteomics finding. More informative than generic protein binding but not a core function. Supporting Evidence: PMID:25468996 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | KEEP AS NON CORE | Summary: Reactome annotation for exocytosis of secretory granule lumen proteins. PKM found in extracellular region via secretion. Reason: PKM can be secreted but extracellular localization is not a primary site of function. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: Reactome annotation for ficolin-rich granule exocytosis. PKM present in extracellular region. Reason: Secondary localization from secretory process. |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | KEEP AS NON CORE | Summary: PKM present in secretory granule lumen per Reactome annotation. Reason: Specialized localization related to secretory function. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: PKM present in ficolin-1-rich granule lumen per Reactome annotation. Reason: Specialized localization in immune cell granules. |
| GO:0070062 extracellular exosome | HDA PMID:12519789 Proteomic and biochemical analyses of human B cell-derived e... | KEEP AS NON CORE | Summary: PKM detected in B cell-derived exosomes by proteomics. Reason: Exosomal localization from proteomics study. Not primary functional location. Supporting Evidence: PMID:12519789 2003 Jan 7. Proteomic and biochemical analyses of human B cell-derived exosomes. |
| GO:0070062 extracellular exosome | HDA PMID:11487543 Intestinal epithelial cells secrete exosome-like vesicles. | KEEP AS NON CORE | Summary: PKM detected in intestinal epithelial cell exosomes. Reason: Exosomal cargo. Not primary functional location. Supporting Evidence: PMID:11487543 Intestinal epithelial cells secrete exosome-like vesicles. |
| GO:1903561 extracellular vesicle | HDA PMID:24769233 Proteomic analysis of cerebrospinal fluid extracellular vesi... | KEEP AS NON CORE | Summary: PKM detected in CSF extracellular vesicles by proteomics. Reason: Extracellular vesicle cargo from proteomics. Supporting Evidence: PMID:24769233 2014 Apr 24. Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: PKM detected in prostatic secretion exosomes. Reason: Exosomal cargo from proteomics. Supporting Evidence: PMID:23533145 2013 Apr 23. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. |
| GO:0031982 vesicle | HDA PMID:19190083 Characterization of exosome-like vesicles released from huma... | KEEP AS NON CORE | Summary: PKM detected in tracheobronchial epithelial exosome-like vesicles. Reason: Vesicular localization from proteomics. Supporting Evidence: PMID:19190083 Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | KEEP AS NON CORE | Summary: PKM detected in sperm nucleus by proteomics. Supports nuclear localization capability. Reason: Nuclear detection in specialized cell type. PKM2-specific function. Supporting Evidence: PMID:21630459 Jun 1. Proteomic characterization of the human sperm nucleus. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: PKM identified in mRNA-binding protein atlas. Supports moonlighting function in translation regulation. Reason: Non-canonical moonlighting function from proteomics study. Supporting Evidence: PMID:22658674 May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | KEEP AS NON CORE | Summary: PKM detected in mitochondrial phosphoproteome. May represent association with mitochondria or contamination. Reason: Unexpected localization from phosphoproteomics. PKM is canonically cytosolic. Supporting Evidence: PMID:20833797 Epub 2010 Sep 10. Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: PKM detected in parotid gland exosomes. Reason: Exosomal cargo from proteomics. Supporting Evidence: PMID:19199708 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: PKM detected in urinary exosomes by proteomics. Reason: Exosomal cargo from proteomics. Supporting Evidence: PMID:19056867 2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes. |
| GO:0023026 MHC class II protein complex binding | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: PKM identified as MHC class II-associated protein in B-cell exosomes. Reason: High-throughput proteomics finding. Specialized immune function context. Supporting Evidence: PMID:20458337 2010 May 11. MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: PKM detected in B-cell exosomes. Reason: Exosomal cargo from proteomics. Supporting Evidence: PMID:20458337 2010 May 11. MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-71670 | ACCEPT | Summary: Reactome annotation for pyruvate kinase reaction. Cytosolic localization correct for glycolytic function. Reason: Core localization for glycolytic function. |
| GO:0004743 pyruvate kinase activity | IDA PMID:20005212 Identification of small molecule inhibitors of pyruvate kina... | ACCEPT | Summary: Study identifying small molecule inhibitors of PKM2. Directly demonstrates pyruvate kinase activity. Reason: Core function with direct experimental evidence. Supporting Evidence: PMID:20005212 Epub 2009 Dec 11. Identification of small molecule inhibitors of pyruvate kinase M2. |
| GO:0070062 extracellular exosome | HDA PMID:21362503 Protein profile of exosomes from trabecular meshwork cells. | KEEP AS NON CORE | Summary: PKM detected in trabecular meshwork cell exosomes. Reason: Exosomal cargo from proteomics. Supporting Evidence: PMID:21362503 Epub 2011 Mar 8. Protein profile of exosomes from trabecular meshwork cells. |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | ACCEPT | Summary: Direct assay evidence for cytoplasmic localization from fusion protein studies. Reason: Core localization for both isoforms. |
| GO:0005634 nucleus | IDA P14618-1 PMID:18191611 Pyruvate kinase isozyme type M2 (PKM2) interacts and coopera... | KEEP AS NON CORE | Summary: PKM2 interacts with Oct-4 in the nucleus and cooperates in regulating transcription. This is PKM2-SPECIFIC nuclear function. Reason: Direct experimental evidence for PKM2-specific nuclear localization during non-canonical transcriptional coactivation, distinct from the canonical cytosolic glycolytic localization. Supporting Evidence: PMID:18191611 PKM2 is an isozyme of pyruvate kinase that is specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. |
| GO:0005737 cytoplasm | IDA PMID:18298799 Modulation of M2-type pyruvate kinase activity by the cytopl... | ACCEPT | Summary: Study showing cytoplasmic PML modulates PKM2 activity. Confirms cytoplasmic localization. Reason: Core localization confirmed by direct evidence. Supporting Evidence: PMID:18298799 cytoplasmic PML (cPML) directly interacts with M2-type pyruvate kinase (PKM2) |
| GO:0005515 protein binding | IPI P14618-1 PMID:18191611 Pyruvate kinase isozyme type M2 (PKM2) interacts and coopera... | MODIFY | Summary: PKM2 interacts with Oct-4 transcription factor. The interaction enhances Oct-4 transcriptional activity. PKM2-SPECIFIC interaction. Reason: Functionally significant interaction with transcription factor. Generic protein binding term is uninformative. Should be more specific (e.g., transcription factor binding). Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:18191611 ectopic expression of the PKM2 enhanced Oct-4-mediated transcription |
| GO:0005515 protein binding | IPI PMID:18298799 Modulation of M2-type pyruvate kinase activity by the cytopl... | REMOVE | Summary: PKM2 interacts with PML tumor suppressor. PML modulates PKM2 tetrameric activity. Reason: Bare GO:0005515 protein binding is uninformative under the protein-binding policy; no specific binding descendant term applies to cytoplasmic PML binding. Supporting Evidence: PMID:18298799 cytoplasmic PML (cPML) directly interacts with M2-type pyruvate kinase (PKM2) |
| GO:0005634 nucleus | IDA P14618-1 PMID:17308100 Nuclear translocation of the tumor marker pyruvate kinase M2... | KEEP AS NON CORE | Summary: PKM2 translocates to nucleus in response to apoptotic stimuli and TT-232. Nuclear translocation induces cell death. PKM2-SPECIFIC function. Reason: Direct experimental evidence for stimulus-dependent, PKM2-specific nuclear translocation, distinct from the canonical cytosolic glycolytic localization. Supporting Evidence: PMID:17308100 Nuclear translocation of PKM2 is sufficient to induce cell death that is caspase independent, isoform specific, and independent of its enzymatic activity. |
| GO:0012501 programmed cell death | IDA P14618-1 PMID:17308100 Nuclear translocation of the tumor marker pyruvate kinase M2... | KEEP AS NON CORE | Summary: Nuclear PKM2 translocation induces programmed cell death. This is a PKM2-SPECIFIC function that is caspase-independent and independent of pyruvate kinase activity. Reason: PKM2-specific non-metabolic function. Not a core function but well-documented. Supporting Evidence: PMID:17308100 Nuclear translocation of PKM2 is sufficient to induce cell death that is caspase independent, isoform specific, and independent of its enzymatic activity. |
| GO:0004743 pyruvate kinase activity | TAS PMID:2854097 Human M2-type pyruvate kinase: cDNA cloning, chromosomal ass... | ACCEPT | Summary: Original cloning of human M2-type pyruvate kinase cDNA. Establishes pyruvate kinase activity as core function. Reason: Core function from original characterization of PKM2. Supporting Evidence: PMID:2854097 Human M2-type pyruvate kinase: cDNA cloning, chromosomal assignment and expression in hepatoma. |
| GO:0004743 pyruvate kinase activity | TAS PMID:2040271 Isolation and characterization of the human pyruvate kinase ... | ACCEPT | Summary: Isolation and characterization of human pyruvate kinase M gene. Reason: Core function from gene characterization. Supporting Evidence: PMID:2040271 Isolation and characterization of the human pyruvate kinase M gene. |
| GO:0004743 pyruvate kinase activity | TAS PMID:2813362 Cytosolic thyroid hormone-binding protein is a monomer of py... | ACCEPT | Summary: Demonstrates PKM is a cytosolic thyroid hormone-binding protein that is a monomer of pyruvate kinase with enzymatic activity. Reason: Core function established in characterization study. Supporting Evidence: PMID:2813362 Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase. |
| GO:0005829 cytosol | NAS PMID:2813362 Cytosolic thyroid hormone-binding protein is a monomer of py... | ACCEPT | Summary: PKM identified as cytosolic thyroid hormone-binding protein. Reason: Core localization established in early characterization. Supporting Evidence: PMID:2813362 Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase. |
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