id: P14618
gene_symbol: PKM
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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):
  - Protein kinase activity (phosphorylates histone H3 at Tyr11)
  - Nuclear translocation and transcription coactivator activity (with HIF-1alpha)
  - These non-glycolytic 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.
alternative_products:
  - name: M2 {ECO:0000303|PubMed:2854097} (M2-PK, PKM2)
    id: P14618-1
  - name: M1 {ECO:0000303|PubMed:2854097} (M1-PK, PKM1)
    id: P14618-2, P14786-1
    sequence_note: VSP_011101
  - name: '3'
    id: P14618-3
    sequence_note: VSP_043370
existing_annotations:
  - term:
      id: GO:0004743
      label: pyruvate kinase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:20847263
          supporting_text: "Paradoxically, decreased pyruvate kinase enzyme activity
            accompanies the expression of PKM2 in rapidly dividing cancer cells and
            tissues."
        - reference_id: file:human/PKM/PKM-deep-research-falcon.md
          supporting_text: "PKM catalyzes the terminal glycolytic step: PEP + ADP -> pyruvate + ATP, coupling high-energy phosphate transfer to ATP production."
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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].
      action: ACCEPT
      reason: >-
        Cytoplasmic localization is correct for both isoforms and represents the primary
        site of
        glycolytic function.
      supported_by:
        - reference_id: PMID:22056988
          supporting_text: "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"
  - term:
      id: GO:0006096
      label: glycolytic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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].
      action: ACCEPT
      reason: >-
        Core function for both isoforms. Both participate in glycolysis though PKM2's
        low activity
        fundamentally alters glycolytic flux in proliferating cells.
      supported_by:
        - reference_id: PMID:20847263
          supporting_text: "The M2 isoform of pyruvate kinase (PKM2) promotes the
            metabolism of glucose by aerobic glycolysis and contributes to anabolic
            metabolism."
  - term:
      id: GO:0032869
      label: cellular response to insulin stimulus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        PKM expression and activity can be regulated by insulin signaling. This is
        a phylogenetically
        conserved function supported by IBA evidence.
      action: KEEP_AS_NON_CORE
      reason: >-
        This represents a regulatory response rather than a core biochemical function.
        PKM participates
        in insulin-mediated metabolic regulation but this is secondary to its primary
        glycolytic function.
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: ACCEPT
      reason: >-
        Correct parent term of ATP binding, which is required for pyruvate kinase
        activity.
        Both isoforms bind nucleotides.
  - term:
      id: GO:0000287
      label: magnesium ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Pyruvate kinase requires Mg2+ as a cofactor [UniProt P14618]. This applies
        to both isoforms.
      action: ACCEPT
      reason: >-
        Mg2+ is an essential cofactor for pyruvate kinase activity. Both isoforms
        require this ion.
  - term:
      id: GO:0003824
      label: catalytic activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        PKM has catalytic activity. This is an overly broad parent term - the specific
        pyruvate kinase activity annotation is more informative.
      action: ACCEPT
      reason: >-
        True but uninformative parent term. Both isoforms have catalytic activity.
  - term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000003
    review:
      summary: >-
        PKM2 (NOT PKM1) has protein threonine kinase activity. PKM2 phosphorylates
        histone H3 at
        Thr-11 (H3T11ph) [PMID:22901803, UniProt]. This is a PKM2-SPECIFIC function
        that occurs
        when PKM2 is in the nuclear dimeric form. PKM1 does NOT have this activity.
      action: MODIFY
      reason: >-
        CRITICAL ISOFORM CONFLATION: This annotation applies ONLY to PKM2 (P14618-1),
        not PKM1.
        The IEA annotation fails to capture this isoform specificity; the requested
        modification is to retain GO:0004674 but add the isoform qualifier
        isoform: P14618-1.
      proposed_replacement_terms:
        - id: GO:0004674
          label: protein serine/threonine kinase activity
      additional_reference_ids:
        - UniProt:P14618
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000116
    review:
      summary: >-
        PKM2 (NOT PKM1) has protein tyrosine kinase activity. PKM2 phosphorylates
        STAT3 at Tyr-705
        [PMID:22306293, UniProt]. This is a PKM2-SPECIFIC function that occurs in
        the nuclear dimeric
        form. PKM1 does NOT have this activity.
      action: MODIFY
      reason: >-
        CRITICAL ISOFORM CONFLATION: This annotation applies ONLY to PKM2 (P14618-1),
        not PKM1.
        The IEA annotation fails to capture this isoform specificity; the requested
        modification is to retain GO:0004713 but add the isoform qualifier
        isoform: P14618-1.
      proposed_replacement_terms:
        - id: GO:0004713
          label: protein tyrosine kinase activity
  - term:
      id: GO:0004715
      label: non-membrane spanning protein tyrosine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000003
    review:
      summary: >-
        PKM2 (NOT PKM1) has non-membrane spanning protein tyrosine kinase activity.
        This is
        consistent with its cytosolic/nuclear localization. PKM1 does NOT have this
        activity.
      action: MODIFY
      reason: >-
        CRITICAL ISOFORM CONFLATION: This annotation applies ONLY to PKM2 (P14618-1),
        not PKM1. The requested modification is to retain GO:0004715 but add the
        isoform qualifier isoform: P14618-1.
      proposed_replacement_terms:
        - id: GO:0004715
          label: non-membrane spanning protein tyrosine kinase activity
  - term:
      id: GO:0004743
      label: pyruvate kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of IBA annotation. Both isoforms have pyruvate kinase activity,
        though with
        vastly different kinetic properties.
      action: ACCEPT
      reason: >-
        Core function for both isoforms. This IEA annotation is redundant with the
        IBA annotation
        but not incorrect.
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        PKM binds ATP/ADP as substrates for pyruvate kinase reaction. Both isoforms
        bind ATP.
      action: ACCEPT
      reason: >-
        Correct annotation for both isoforms as ATP/ADP binding is essential for pyruvate
        kinase activity.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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.
      action: MODIFY
      reason: >-
        CRITICAL ISOFORM CONFLATION: Nuclear localization applies ONLY to PKM2 (P14618-1);
        the requested modification is to retain GO:0005634 but add the isoform
        qualifier isoform: P14618-1.
        PMID:22056988 explicitly states "PKM1 failed to translocate into the nucleus
        upon EGF stimulation".
      proposed_replacement_terms:
        - id: GO:0005634
          label: nucleus
      supported_by:
        - reference_id: PMID:22056988
          supporting_text: "In addition, PKM1 failed to translocate into the nucleus
            upon EGF stimulation"
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        Both PKM1 and PKM2 localize to the cytoplasm. This is the primary site of
        glycolytic function.
      action: ACCEPT
      reason: >-
        Correct for both isoforms. Cytoplasmic localization is the primary location
        for glycolytic function.
  - term:
      id: GO:0006096
      label: glycolytic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of IBA annotation. Both isoforms participate in glycolysis.
      action: ACCEPT
      reason: >-
        Core function for both isoforms. Redundant with IBA annotation but not incorrect.
  - term:
      id: GO:0006417
      label: regulation of translation
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a non-canonical moonlighting function of PKM2 based on similarity
        evidence.
        Not a core function.
  - term:
      id: GO:0016301
      label: kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        PKM has kinase activity - pyruvate kinase activity for both isoforms, and
        protein kinase
        activity for PKM2 only. This is a broad parent term.
      action: ACCEPT
      reason: >-
        True but uninformative parent term encompassing both pyruvate kinase and protein
        kinase activities.
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        PKM has transferase activity (phosphotransferase). This is a very broad parent
        term.
      action: ACCEPT
      reason: >-
        True but uninformative high-level parent term. Both isoforms have transferase
        activity.
  - term:
      id: GO:0030955
      label: potassium ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Pyruvate kinase requires K+ as a cofactor [UniProt P14618]. This applies to
        both isoforms.
      action: ACCEPT
      reason: >-
        K+ is an essential cofactor for pyruvate kinase activity. Both isoforms require
        this ion.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        PKM binds metal ions (Mg2+, K+) as cofactors. Parent term of magnesium and
        potassium binding.
      action: ACCEPT
      reason: >-
        True parent term. Both isoforms bind metal ion cofactors.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12620389
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from Y2H screen. Does not provide functional insight
        into
        PKM's core activities. More specific interaction terms would be more informative.
      supported_by:
        - reference_id: PMID:12620389
          supporting_text: Novel raf kinase protein-protein interactions found 
            by an exhaustive yeast two-hybrid analysis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17500595
    review:
      summary: >-
        PKM identified as a Huntingtin interacting protein and potential modifier
        of
        neurodegeneration. High-throughput interactome study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from interactome study. Does not distinguish between
        isoforms or provide functional context.
      supported_by:
        - reference_id: PMID:17500595
          supporting_text: Huntingtin interacting proteins are genetic modifiers
            of neurodegeneration.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17620599
    review:
      summary: >-
        PKM identified in beta-arrestin interactome study. High-throughput proteomics.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from proteomics study. Uninformative without functional
        context.
      supported_by:
        - reference_id: PMID:17620599
          supporting_text: Functional specialization of beta-arrestin 
            interactions revealed by proteomic analysis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18519040
    review:
      summary: >-
        Isoform-specific interaction of pyruvate kinase with HCV NS5B. The study specifically
        examines PKM2 interaction with viral protein.
      action: KEEP_AS_NON_CORE
      reason: >-
        Interaction with viral protein is interesting for host-pathogen biology but
        not a
        core function. Appears to be PKM2-specific based on the study context.
      supported_by:
        - reference_id: PMID:18519040
          supporting_text: Epub 2008 Jun 2. Isoform-specific interaction of 
            pyruvate kinase with hepatitis C virus NS5B.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21044950
    review:
      summary: >-
        PKM identified in telomere signaling regulator screen. High-throughput study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from screening study. Lacks functional specificity.
      supported_by:
        - reference_id: PMID:21044950
          supporting_text: Epub 2010 Nov 2. Genome-wide YFP fluorescence 
            complementation screen identifies new regulators for telomere 
            signaling in human cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21725354
    review:
      summary: >-
        Death-associated protein kinase (DAPK) binds and activates pyruvate kinase.
        This is functionally relevant for PKM regulation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Functionally relevant interaction but the generic protein binding term is
        uninformative.
        Would be better captured by a more specific term or in the regulation context.
      supported_by:
        - reference_id: PMID:21725354
          supporting_text: Death-associated protein kinase increases glycolytic 
            rate through binding and activation of pyruvate kinase.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22056988
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0008013
          label: beta-catenin binding
      supported_by:
        - reference_id: PMID:22056988
          supporting_text: "EGF stimulation resulted in an interaction between endogenous
            PKM2 and beta-catenin in the nuclear, but not cytosolic, fraction"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22898364
    review:
      summary: >-
        PKM identified in virus-host interactome study using protein complementation
        assay.
        High-throughput screening.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from high-throughput viral interactome study.
      supported_by:
        - reference_id: PMID:22898364
          supporting_text: Aug 8. Comparative analysis of virus-host 
            interactomes with a mammalian high-throughput protein 
            complementation assay based on Gaussia princeps luciferase.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: >-
        PKM identified in neurodegenerative disease protein interactome mapping study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from disease-focused interactome study.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9990017
    review:
      summary: >-
        HPV-16 E7 oncoprotein modulates M2-type pyruvate kinase activity. E7 binding
        promotes
        PKM2 homodimerization [UniProt].
      action: KEEP_AS_NON_CORE
      reason: >-
        Interaction with viral oncoprotein is relevant for understanding PKM2 in cancer
        but represents host-pathogen interaction rather than core function.
      supported_by:
        - reference_id: PMID:9990017
          supporting_text: Modulation of type M2 pyruvate kinase activity by the
            human papillomavirus type 16 E7 oncoprotein.
  - term:
      id: GO:0003729
      label: mRNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        PKM2 may bind mRNAs as part of its moonlighting function in translation regulation
        [UniProt, by similarity]. Associates with ER-bound ribosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Non-canonical moonlighting function of PKM2 based on similarity evidence.
        Not a core function.
  - term:
      id: GO:0005791
      label: rough endoplasmic reticulum
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        PKM2 may associate with rough ER as part of its translation regulation function
        [UniProt, by similarity].
      action: KEEP_AS_NON_CORE
      reason: >-
        Associated with moonlighting function in translation regulation. Not a primary
        localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Both PKM1 and PKM2 are cytosolic enzymes where they perform glycolysis.
      action: ACCEPT
      reason: >-
        Correct localization for both isoforms. Primary site of glycolytic activity.
  - term:
      id: GO:0005929
      label: cilium
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        PKM localization to cilium based on ortholog evidence. Limited direct evidence.
      action: KEEP_AS_NON_CORE
      reason: >-
        Ortholog-based evidence for specialized localization. Not a primary site of
        function.
  - term:
      id: GO:0061621
      label: canonical glycolysis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Both isoforms participate in canonical glycolysis. PKM catalyzes the final
        step
        converting PEP to pyruvate.
      action: ACCEPT
      reason: >-
        Core function for both isoforms. More specific than generic glycolytic process
        term.
  - term:
      id: GO:2000767
      label: positive regulation of cytoplasmic translation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        PKM2 may positively regulate translation of ER-destined mRNAs [UniProt, by
        similarity].
        Moonlighting function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Non-canonical moonlighting function based on similarity evidence. Not a core
        function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Direct assay evidence for cytosolic localization based on immunofluorescence.
        Both isoforms are cytosolic.
      action: ACCEPT
      reason: >-
        Validated cytosolic localization. Primary site of glycolytic function for
        both isoforms.
  - term:
      id: GO:0004743
      label: pyruvate kinase activity
    evidence_type: IDA
    original_reference_id: PMID:20847263
    review:
      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.
      action: ACCEPT
      reason: >-
        Core function with direct experimental evidence. Both isoforms have activity
        but with
        different kinetic properties.
      supported_by:
        - reference_id: PMID:20847263
          supporting_text: "Paradoxically, decreased pyruvate kinase enzyme activity
            accompanies the expression of PKM2 in rapidly dividing cancer cells and
            tissues."
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9766062
    review:
      summary: >-
        Reactome pathway annotation for PKM and TGIF2 binding CDH1 gene promoter.
        This nuclear
        function is PKM2-specific based on literature evidence.
      action: MODIFY
      reason: >-
        ISOFORM CONFLATION: Nucleoplasm localization is PKM2-specific. PKM1 does not
        translocate to nucleus. The requested modification is to retain GO:0005654
        but add the isoform qualifier isoform: P14618-1.
      proposed_replacement_terms:
        - id: GO:0005654
          label: nucleoplasm
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9861640
    review:
      summary: >-
        Reactome annotation for CTLH E3 ligase ubiquitinating PKM-1. Cytosolic localization
        is correct for both isoforms.
      action: ACCEPT
      reason: >-
        Correct localization for both isoforms.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27573352
    review:
      summary: >-
        TSC22D2 interacts with PKM2 and inhibits cell growth in colorectal cancer.
        The interaction reduces nuclear PKM2 levels and represses cyclin D1 transcription.
      action: KEEP_AS_NON_CORE
      reason: >-
        Functionally relevant interaction specific to PKM2. Generic protein binding
        term
        lacks specificity.
      supported_by:
        - reference_id: PMID:27573352
          supporting_text: TSC22D2 interacts with PKM2 and inhibits cell growth 
            in colorectal cancer.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:27573352
    review:
      summary: >-
        Direct evidence for PKM nuclear localization. The study specifically examines
        PKM2
        (isoform M2) nuclear localization and its regulation by TSC22D2.
      action: ACCEPT
      reason: >-
        Direct experimental evidence for nuclear localization. This is PKM2-specific
        function
        but IDA evidence is strong.
      supported_by:
        - reference_id: PMID:27573352
          supporting_text: TSC22D2 interacts with PKM2 and inhibits cell growth 
            in colorectal cancer.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:27573352
    review:
      summary: >-
        Direct evidence for PKM cytoplasmic localization. Both isoforms are cytoplasmic.
      action: ACCEPT
      reason: >-
        Correct for both isoforms. Primary site of glycolytic function.
      supported_by:
        - reference_id: PMID:27573352
          supporting_text: TSC22D2 interacts with PKM2 and inhibits cell growth 
            in colorectal cancer.
  - term:
      id: GO:0003729
      label: mRNA binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Sequence similarity-based annotation for mRNA binding. Moonlighting function
        of PKM2.
      action: KEEP_AS_NON_CORE
      reason: >-
        Non-canonical function based on similarity. Not a core function.
  - term:
      id: GO:0005791
      label: rough endoplasmic reticulum
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Sequence similarity-based annotation. Associated with translation regulation
        moonlighting function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Non-canonical localization associated with moonlighting function.
  - term:
      id: GO:2000767
      label: positive regulation of cytoplasmic translation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Sequence similarity-based annotation for translation regulation. Moonlighting
        function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Non-canonical moonlighting function based on sequence similarity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27199445
    review:
      summary: >-
        JMJD8 interacts with PKM2 and regulates angiogenic sprouting and cellular
        metabolism.
      action: KEEP_AS_NON_CORE
      reason: >-
        Functionally relevant interaction but generic protein binding term is uninformative.
      supported_by:
        - reference_id: PMID:27199445
          supporting_text: JMJD8 Regulates Angiogenic Sprouting and Cellular 
            Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial 
            Cells.
  - term:
      id: GO:1903672
      label: positive regulation of sprouting angiogenesis
    evidence_type: IMP
    original_reference_id: PMID:27199445
    review:
      summary: >-
        PKM regulates angiogenic sprouting through interaction with JMJD8 in endothelial
        cells.
        Likely PKM2-mediated based on cancer/proliferation context.
      action: KEEP_AS_NON_CORE
      reason: >-
        Pleiotropic downstream effect in specialized cell type context. Not a core
        function
        of PKM.
      supported_by:
        - reference_id: PMID:27199445
          supporting_text: JMJD8 Regulates Angiogenic Sprouting and Cellular 
            Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial 
            Cells.
  - term:
      id: GO:0045296
      label: cadherin binding
    evidence_type: HDA
    original_reference_id: PMID:25468996
    review:
      summary: >-
        High-throughput proteomics study of E-cadherin interactome. PKM identified
        as
        an interactor.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput proteomics finding. More informative than generic protein
        binding
        but not a core function.
      supported_by:
        - reference_id: PMID:25468996
          supporting_text: E-cadherin interactome complexity and robustness 
            resolved by quantitative proteomics.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6798748
    review:
      summary: >-
        Reactome annotation for exocytosis of secretory granule lumen proteins. PKM
        found
        in extracellular region via secretion.
      action: KEEP_AS_NON_CORE
      reason: >-
        PKM can be secreted but extracellular localization is not a primary site of
        function.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800434
    review:
      summary: >-
        Reactome annotation for ficolin-rich granule exocytosis. PKM present in extracellular
        region.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary localization from secretory process.
  - term:
      id: GO:0034774
      label: secretory granule lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6798748
    review:
      summary: >-
        PKM present in secretory granule lumen per Reactome annotation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specialized localization related to secretory function.
  - term:
      id: GO:1904813
      label: ficolin-1-rich granule lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800434
    review:
      summary: >-
        PKM present in ficolin-1-rich granule lumen per Reactome annotation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specialized localization in immune cell granules.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:12519789
    review:
      summary: >-
        PKM detected in B cell-derived exosomes by proteomics.
      action: KEEP_AS_NON_CORE
      reason: >-
        Exosomal localization from proteomics study. Not primary functional location.
      supported_by:
        - reference_id: PMID:12519789
          supporting_text: 2003 Jan 7. Proteomic and biochemical analyses of 
            human B cell-derived exosomes.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:11487543
    review:
      summary: >-
        PKM detected in intestinal epithelial cell exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Exosomal cargo. Not primary functional location.
      supported_by:
        - reference_id: PMID:11487543
          supporting_text: Intestinal epithelial cells secrete exosome-like 
            vesicles.
  - term:
      id: GO:1903561
      label: extracellular vesicle
    evidence_type: HDA
    original_reference_id: PMID:24769233
    review:
      summary: >-
        PKM detected in CSF extracellular vesicles by proteomics.
      action: KEEP_AS_NON_CORE
      reason: >-
        Extracellular vesicle cargo from proteomics.
      supported_by:
        - reference_id: PMID:24769233
          supporting_text: '2014 Apr 24. Proteomic analysis of cerebrospinal fluid
            extracellular vesicles: a comprehensive dataset.'
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:23533145
    review:
      summary: >-
        PKM detected in prostatic secretion exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Exosomal cargo from proteomics.
      supported_by:
        - reference_id: PMID:23533145
          supporting_text: 2013 Apr 23. In-depth proteomic analyses of exosomes 
            isolated from expressed prostatic secretions in urine.
  - term:
      id: GO:0031982
      label: vesicle
    evidence_type: HDA
    original_reference_id: PMID:19190083
    review:
      summary: >-
        PKM detected in tracheobronchial epithelial exosome-like vesicles.
      action: KEEP_AS_NON_CORE
      reason: >-
        Vesicular localization from proteomics.
      supported_by:
        - reference_id: PMID:19190083
          supporting_text: 'Characterization of exosome-like vesicles released from
            human tracheobronchial ciliated epithelium: a possible role in innate
            defense.'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: HDA
    original_reference_id: PMID:21630459
    review:
      summary: >-
        PKM detected in sperm nucleus by proteomics. Supports nuclear localization
        capability.
      action: KEEP_AS_NON_CORE
      reason: >-
        Nuclear detection in specialized cell type. PKM2-specific function.
      supported_by:
        - reference_id: PMID:21630459
          supporting_text: Jun 1. Proteomic characterization of the human sperm 
            nucleus.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22658674
    review:
      summary: >-
        PKM identified in mRNA-binding protein atlas. Supports moonlighting function
        in
        translation regulation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Non-canonical moonlighting function from proteomics study.
      supported_by:
        - reference_id: PMID:22658674
          supporting_text: May 31. Insights into RNA biology from an atlas of 
            mammalian mRNA-binding proteins.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HDA
    original_reference_id: PMID:20833797
    review:
      summary: >-
        PKM detected in mitochondrial phosphoproteome. May represent association with
        mitochondria or contamination.
      action: KEEP_AS_NON_CORE
      reason: >-
        Unexpected localization from phosphoproteomics. PKM is canonically cytosolic.
      supported_by:
        - reference_id: PMID:20833797
          supporting_text: Epub 2010 Sep 10. Phosphoproteome analysis of 
            functional mitochondria isolated from resting human muscle reveals 
            extensive phosphorylation of inner membrane protein complexes and 
            enzymes.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19199708
    review:
      summary: >-
        PKM detected in parotid gland exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Exosomal cargo from proteomics.
      supported_by:
        - reference_id: PMID:19199708
          supporting_text: Proteomic analysis of human parotid gland exosomes by
            multidimensional protein identification technology (MudPIT).
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19056867
    review:
      summary: >-
        PKM detected in urinary exosomes by proteomics.
      action: KEEP_AS_NON_CORE
      reason: >-
        Exosomal cargo from proteomics.
      supported_by:
        - reference_id: PMID:19056867
          supporting_text: 2008 Dec 3. Large-scale proteomics and 
            phosphoproteomics of urinary exosomes.
  - term:
      id: GO:0023026
      label: MHC class II protein complex binding
    evidence_type: HDA
    original_reference_id: PMID:20458337
    review:
      summary: >-
        PKM identified as MHC class II-associated protein in B-cell exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput proteomics finding. Specialized immune function context.
      supported_by:
        - reference_id: PMID:20458337
          supporting_text: 2010 May 11. MHC class II-associated proteins in 
            B-cell exosomes and potential functional implications for exosome 
            biogenesis.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:20458337
    review:
      summary: >-
        PKM detected in B-cell exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Exosomal cargo from proteomics.
      supported_by:
        - reference_id: PMID:20458337
          supporting_text: 2010 May 11. MHC class II-associated proteins in 
            B-cell exosomes and potential functional implications for exosome 
            biogenesis.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-71670
    review:
      summary: >-
        Reactome annotation for pyruvate kinase reaction. Cytosolic localization correct
        for glycolytic function.
      action: ACCEPT
      reason: >-
        Core localization for glycolytic function.
  - term:
      id: GO:0004743
      label: pyruvate kinase activity
    evidence_type: IDA
    original_reference_id: PMID:20005212
    review:
      summary: >-
        Study identifying small molecule inhibitors of PKM2. Directly demonstrates
        pyruvate kinase activity.
      action: ACCEPT
      reason: >-
        Core function with direct experimental evidence.
      supported_by:
        - reference_id: PMID:20005212
          supporting_text: Epub 2009 Dec 11. Identification of small molecule 
            inhibitors of pyruvate kinase M2.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:21362503
    review:
      summary: >-
        PKM detected in trabecular meshwork cell exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        Exosomal cargo from proteomics.
      supported_by:
        - reference_id: PMID:21362503
          supporting_text: Epub 2011 Mar 8. Protein profile of exosomes from 
            trabecular meshwork cells.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000054
    review:
      summary: >-
        Direct assay evidence for cytoplasmic localization from fusion protein studies.
      action: ACCEPT
      reason: >-
        Core localization for both isoforms.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:18191611
    review:
      summary: >-
        PKM2 interacts with Oct-4 in the nucleus and cooperates in regulating transcription.
        This is PKM2-SPECIFIC nuclear function.
      action: ACCEPT
      reason: >-
        Direct experimental evidence for PKM2 nuclear localization and function.
      supported_by:
        - reference_id: PMID:18191611
          supporting_text: "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."
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:18298799
    review:
      summary: >-
        Study showing cytoplasmic PML modulates PKM2 activity. Confirms cytoplasmic
        localization.
      action: ACCEPT
      reason: >-
        Core localization confirmed by direct evidence.
      supported_by:
        - reference_id: PMID:18298799
          supporting_text: "cytoplasmic PML (cPML) directly interacts with M2-type
            pyruvate kinase (PKM2)"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18191611
    review:
      summary: >-
        PKM2 interacts with Oct-4 transcription factor. The interaction enhances Oct-4
        transcriptional activity. PKM2-SPECIFIC interaction.
      action: MODIFY
      reason: >-
        Functionally significant interaction with transcription factor. Generic protein
        binding
        term is uninformative. Should be more specific (e.g., transcription factor
        binding).
      proposed_replacement_terms:
        - id: GO:0140297
          label: DNA-binding transcription factor binding
      supported_by:
        - reference_id: PMID:18191611
          supporting_text: "ectopic expression of the PKM2 enhanced Oct-4-mediated
            transcription"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18298799
    review:
      summary: >-
        PKM2 interacts with PML tumor suppressor. PML modulates PKM2 tetrameric activity.
      action: KEEP_AS_NON_CORE
      reason: >-
        Functionally relevant interaction for PKM2 regulation but generic protein
        binding
        term is uninformative.
      supported_by:
        - reference_id: PMID:18298799
          supporting_text: "cytoplasmic PML (cPML) directly interacts with M2-type
            pyruvate kinase (PKM2)"
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17308100
    review:
      summary: >-
        PKM2 translocates to nucleus in response to apoptotic stimuli and TT-232.
        Nuclear
        translocation induces cell death. PKM2-SPECIFIC function.
      action: ACCEPT
      reason: >-
        Direct experimental evidence for PKM2-specific nuclear translocation.
      supported_by:
        - reference_id: PMID:17308100
          supporting_text: "Nuclear translocation of PKM2 is sufficient to induce
            cell death that is caspase independent, isoform specific, and independent
            of its enzymatic activity."
  - term:
      id: GO:0012501
      label: programmed cell death
    evidence_type: IDA
    original_reference_id: PMID:17308100
    review:
      summary: >-
        Nuclear PKM2 translocation induces programmed cell death. This is a PKM2-SPECIFIC
        function that is caspase-independent and independent of pyruvate kinase activity.
      action: KEEP_AS_NON_CORE
      reason: >-
        PKM2-specific non-metabolic function. Not a core function but well-documented.
      supported_by:
        - reference_id: PMID:17308100
          supporting_text: "Nuclear translocation of PKM2 is sufficient to induce
            cell death that is caspase independent, isoform specific, and independent
            of its enzymatic activity."
  - term:
      id: GO:0004743
      label: pyruvate kinase activity
    evidence_type: TAS
    original_reference_id: PMID:2854097
    review:
      summary: >-
        Original cloning of human M2-type pyruvate kinase cDNA. Establishes pyruvate
        kinase
        activity as core function.
      action: ACCEPT
      reason: >-
        Core function from original characterization of PKM2.
      supported_by:
        - reference_id: PMID:2854097
          supporting_text: 'Human M2-type pyruvate kinase: cDNA cloning, chromosomal
            assignment and expression in hepatoma.'
  - term:
      id: GO:0004743
      label: pyruvate kinase activity
    evidence_type: TAS
    original_reference_id: PMID:2040271
    review:
      summary: >-
        Isolation and characterization of human pyruvate kinase M gene.
      action: ACCEPT
      reason: >-
        Core function from gene characterization.
      supported_by:
        - reference_id: PMID:2040271
          supporting_text: Isolation and characterization of the human pyruvate 
            kinase M gene.
  - term:
      id: GO:0004743
      label: pyruvate kinase activity
    evidence_type: TAS
    original_reference_id: PMID:2813362
    review:
      summary: >-
        Demonstrates PKM is a cytosolic thyroid hormone-binding protein that is a
        monomer
        of pyruvate kinase with enzymatic activity.
      action: ACCEPT
      reason: >-
        Core function established in characterization study.
      supported_by:
        - reference_id: PMID:2813362
          supporting_text: Cytosolic thyroid hormone-binding protein is a 
            monomer of pyruvate kinase.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: NAS
    original_reference_id: PMID:2813362
    review:
      summary: >-
        PKM identified as cytosolic thyroid hormone-binding protein.
      action: ACCEPT
      reason: >-
        Core localization established in early characterization.
      supported_by:
        - reference_id: PMID:2813362
          supporting_text: Cytosolic thyroid hormone-binding protein is a 
            monomer of pyruvate kinase.
core_functions:
  - molecular_function:
      id: GO:0004743
      label: pyruvate kinase activity
    description: >-
      PKM catalyzes the final rate-limiting step of glycolysis, transferring a phosphoryl
      group
      from phosphoenolpyruvate (PEP) to ADP to generate pyruvate and ATP. CRITICAL
      ISOFORM
      DISTINCTION: PKM1 (P14618-2) is constitutively active with HIGH activity in
      adult tissues
      (muscle, brain, heart). PKM2 (P14618-1) has LOW basal activity requiring allosteric
      activation by fructose-1,6-bisphosphate, and is expressed in embryonic tissues
      and cancer
      cells. PKM2's low activity allows glycolytic intermediates to accumulate for
      biosynthetic
      pathways - the metabolic basis of the Warburg effect.
    supported_by:
      - reference_id: file:human/PKM/PKM-deep-research-falcon.md
        supporting_text: "PKM catalyzes the terminal glycolytic step: PEP + ADP -> pyruvate + ATP, coupling high-energy phosphate transfer to ATP production."
  - molecular_function:
      id: GO:0004713
      label: protein tyrosine kinase activity
    description: >-
      PKM2-SPECIFIC FUNCTION (not present in PKM1): Nuclear dimeric PKM2 acts as a
      protein
      tyrosine kinase, phosphorylating STAT3 at Tyr-705 to activate transcription.
      This
      non-metabolic moonlighting function contributes to cancer cell proliferation
      and
      tumorigenesis. PKM1 does NOT have this activity.
    supported_by:
      - reference_id: file:human/PKM/PKM-deep-research-falcon.md
        supporting_text: "The report summarizes noncanonical PKM2 protein-kinase roles, including tyrosine kinase activity linked to STAT3 Tyr-705 phosphorylation and transcriptional activation."
  - molecular_function:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    description: >-
      PKM2-SPECIFIC FUNCTION (not present in PKM1): Nuclear dimeric PKM2 phosphorylates
      histone H3 at Thr-11 (H3T11ph), promoting gene transcription and tumorigenesis.
      This protein kinase activity requires nuclear translocation and dimerization,
      distinct from its cytoplasmic glycolytic function. PKM1 does NOT have this activity.
    supported_by:
      - reference_id: file:human/PKM/PKM-deep-research-falcon.md
        supporting_text: "The report summarizes noncanonical PKM2 kinase functions, including histone H3 phosphorylation and a 2024 EMBO Journal finding that PKM2 can act as a PEP-dependent histidine kinase toward PGAM1 H11."
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000003
    title: Gene Ontology annotation based on Enzyme Commission mapping
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000054
    title: Gene Ontology annotation based on curation of intracellular 
      localizations of expressed fusion proteins in living cells
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000116
    title: Automatic Gene Ontology annotation based on Rhea mapping
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: file:human/PKM/PKM-deep-research-falcon.md
    title: Falcon deep research report for human PKM
    findings:
      - statement: PKM encodes pyruvate kinase M1/M2, with canonical activity catalyzing PEP + ADP to pyruvate + ATP in the terminal ATP-generating step of glycolysis.
      - statement: The report distinguishes the core glycolytic enzyme function from PKM2-specific noncanonical kinase and transcription-associated activities.
  - id: PMID:11487543
    title: Intestinal epithelial cells secrete exosome-like vesicles.
    findings: []
  - id: PMID:12519789
    title: Proteomic and biochemical analyses of human B cell-derived exosomes. 
      Potential implications for their function and multivesicular body 
      formation.
    findings: []
  - id: PMID:12620389
    title: Novel raf kinase protein-protein interactions found by an exhaustive 
      yeast two-hybrid analysis.
    findings: []
  - id: PMID:17308100
    title: Nuclear translocation of the tumor marker pyruvate kinase M2 induces 
      programmed cell death.
    findings: []
  - id: PMID:17500595
    title: Huntingtin interacting proteins are genetic modifiers of 
      neurodegeneration.
    findings: []
  - id: PMID:17620599
    title: Functional specialization of beta-arrestin interactions revealed by 
      proteomic analysis.
    findings: []
  - id: PMID:18191611
    title: Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with 
      Oct-4 in regulating transcription.
    findings: []
  - id: PMID:18298799
    title: Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML
      tumor suppressor protein.
    findings: []
  - id: PMID:18519040
    title: Isoform-specific interaction of pyruvate kinase with hepatitis C 
      virus NS5B.
    findings: []
  - id: PMID:19056867
    title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
    findings: []
  - id: PMID:19190083
    title: 'Characterization of exosome-like vesicles released from human tracheobronchial
      ciliated epithelium: a possible role in innate defense.'
    findings: []
  - id: PMID:19199708
    title: Proteomic analysis of human parotid gland exosomes by 
      multidimensional protein identification technology (MudPIT).
    findings: []
  - id: PMID:20005212
    title: Identification of small molecule inhibitors of pyruvate kinase M2.
    findings: []
  - id: PMID:2040271
    title: Isolation and characterization of the human pyruvate kinase M gene.
    findings: []
  - id: PMID:20458337
    title: MHC class II-associated proteins in B-cell exosomes and potential 
      functional implications for exosome biogenesis.
    findings: []
  - id: PMID:20833797
    title: Phosphoproteome analysis of functional mitochondria isolated from 
      resting human muscle reveals extensive phosphorylation of inner membrane 
      protein complexes and enzymes.
    findings: []
  - id: PMID:20847263
    title: Evidence for an alternative glycolytic pathway in rapidly 
      proliferating cells.
    findings: []
  - id: PMID:21044950
    title: Genome-wide YFP fluorescence complementation screen identifies new 
      regulators for telomere signaling in human cells.
    findings: []
  - id: PMID:21362503
    title: Protein profile of exosomes from trabecular meshwork cells.
    findings: []
  - id: PMID:21630459
    title: Proteomic characterization of the human sperm nucleus.
    findings: []
  - id: PMID:21725354
    title: Death-associated protein kinase increases glycolytic rate through 
      binding and activation of pyruvate kinase.
    findings: []
  - id: PMID:22056988
    title: Nuclear PKM2 regulates β-catenin transactivation upon EGFR 
      activation.
    findings: []
  - id: PMID:22658674
    title: Insights into RNA biology from an atlas of mammalian mRNA-binding 
      proteins.
    findings: []
  - id: PMID:22898364
    title: Comparative analysis of virus-host interactomes with a mammalian 
      high-throughput protein complementation assay based on Gaussia princeps 
      luciferase.
    findings: []
  - id: PMID:23533145
    title: In-depth proteomic analyses of exosomes isolated from expressed 
      prostatic secretions in urine.
    findings: []
  - id: PMID:24769233
    title: 'Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive
      dataset.'
    findings: []
  - id: PMID:25468996
    title: E-cadherin interactome complexity and robustness resolved by 
      quantitative proteomics.
    findings: []
  - id: PMID:27199445
    title: JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by 
      Interacting With Pyruvate Kinase M2 in Endothelial Cells.
    findings: []
  - id: PMID:27573352
    title: TSC22D2 interacts with PKM2 and inhibits cell growth in colorectal 
      cancer.
    findings: []
  - id: PMID:2813362
    title: Cytosolic thyroid hormone-binding protein is a monomer of pyruvate 
      kinase.
    findings: []
  - id: PMID:2854097
    title: 'Human M2-type pyruvate kinase: cDNA cloning, chromosomal assignment and
      expression in hepatoma.'
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:9990017
    title: Modulation of type M2 pyruvate kinase activity by the human 
      papillomavirus type 16 E7 oncoprotein.
    findings: []
  - id: Reactome:R-HSA-6798748
    title: Exocytosis of secretory granule lumen proteins
    findings: []
  - id: Reactome:R-HSA-6800434
    title: Exocytosis of ficolin-rich granule lumen proteins
    findings: []
  - id: Reactome:R-HSA-71670
    title: Pyruvate kinase dephosphorylates PEP to PYR
    findings: []
  - id: Reactome:R-HSA-9766062
    title: PKM and TGIF2 bind CDH1 gene promoter
    findings: []
  - id: Reactome:R-HSA-9861640
    title: CTLH E3 ligase ubiquitinates PKM-1
    findings: []