id: P24864
gene_symbol: CCNE1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CCNE1 encodes cyclin E1, a regulatory subunit of the cyclin-dependent kinase CDK2.
  Cyclin E1 binds and activates CDK2, driving phosphorylation of key substrates such
  as RB1 to promote the G1/S transition of the cell cycle and commitment to S-phase
  entry. Cyclin E1 itself has no catalytic activity; its role is to confer substrate
  specificity and temporal activation on CDK2. The protein is predominantly nuclear
  and its abundance is tightly regulated by SCF-FBXW7-dependent ubiquitin-mediated
  proteolysis, triggered by phosphodegron motifs phosphorylated by CDK2 and GSK3.
  CCNE1 amplification and overexpression are frequent in cancers, particularly
  high-grade serous ovarian cancer (~22% of TCGA cases), where they drive replication
  stress and genomic instability.
existing_annotations:
  - term:
      id: GO:0000082
      label: G1/S transition of mitotic cell cycle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Core function. Cyclin E1 is the canonical regulator of G1/S transition via
        CDK2 activation. Extensively supported by phylogenetic inference (IBA) and
        all literature.
      action: ACCEPT
      reason: >-
        G1/S transition is the defining biological process for cyclin E1. The deep
        research (CCNE1-deep-research-falcon.md) confirms "Cyclin E1 is a non-enzymatic
        regulatory subunit whose primary molecular function is to bind and activate
        CDK2, thereby promoting late G1 progression and G1/S transition"
        (kasirzadeh2024targetingcdk2to). IBA annotations for such core functions
        are typically well-reviewed.
      supported_by:
        - reference_id: PMID:15838514
          supporting_text: >-
            Cyclin E-Cdk2 has long been considered an essential and master regulator of
            progression through G1 phase of the cell cycle
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Cyclin E1 is a nuclear protein as established by multiple lines of evidence
        including the UniProt record which states "Nucleus" with experimental evidence
        from PMID:7739542.
      action: ACCEPT
      reason: >-
        Nuclear localization of cyclin E1 is well established. UniProt states
        "SUBCELLULAR LOCATION: Nucleus" with experimental evidence. IBA annotation
        is consistent.
      supported_by:
        - reference_id: PMID:19942931
          supporting_text: >-
            Mtd expression in proliferating cells colocalized with cyclin E1, a G(1)/S
            phase cell cycle regulator
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Cyclin E1 is also found in the cytoplasm. IHC studies show both nuclear and
        cytoplasmic localization, and the deep research notes nucleocytoplasmic
        shuttling.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization is supported by IHC evidence showing "cytoplasmic
        cyclin E1 was frequently high (70% high vs 30% low)" in ovarian cancer
        (lashen2024theclinicopathologicalsignificance). Cyclin E and CDK2 are
        known to shuttle between nucleus and cytoplasm
        (chen2025targetingcdk2and). IBA annotation is consistent.
  - term:
      id: GO:0016538
      label: cyclin-dependent protein serine/threonine kinase regulator activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Core molecular function of cyclin E1. It is a non-enzymatic regulatory subunit
        that binds and activates CDK2, a cyclin-dependent serine/threonine kinase.
      action: ACCEPT
      reason: >-
        This is the defining molecular function of cyclin E1. It does not have kinase
        activity itself but activates CDK2. PMID:8207080 confirms "Cyclin E is a
        regulatory subunit of the cdc2-related protein kinase cdk2." The IBA
        annotation is at the right level of specificity.
      supported_by:
        - reference_id: PMID:8207080
          supporting_text: >-
            Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2,
            which is activated shortly before S-phase entry, thus defining it as a G1
            cyclin
  - term:
      id: GO:0097134
      label: cyclin E1-CDK2 complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Cyclin E1 is a defining component of the cyclin E1-CDK2 complex. Crystal
        structure of the complex has been solved (PDB:1W98, PMID:15660127).
      action: ACCEPT
      reason: >-
        UniProt states "Interacts with CDK2 protein kinase to form a serine/threonine
        kinase holoenzyme complex." Multiple crystal structures confirm this
        (PDB:1W98). ComplexPortal entry CPX-2015 explicitly defines the
        Cyclin E1-CDK2 complex.
  - term:
      id: GO:0005815
      label: microtubule organizing center
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Cyclin E-CDK2 is known to play a role in centrosome duplication, and
        localization to centrosomes (microtubule organizing centers) has been reported
        in the literature for cyclin E in model organisms. The IBA annotation reflects
        phylogenetic inference from orthologs.
      action: ACCEPT
      reason: >-
        Cyclin E-CDK2 activity is required for centrosome duplication, and cyclin E
        has been shown to localize to centrosomes. This is supported by the broader
        cell cycle biology literature and is phylogenetically conserved (IBA).
  - term:
      id: GO:1900087
      label: positive regulation of G1/S transition of mitotic cell cycle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Cyclin E1 positively regulates G1/S transition by activating CDK2, which
        phosphorylates RB1 to release E2F transcription factors for S-phase gene
        expression.
      action: ACCEPT
      reason: >-
        This is a core function. The deep research confirms "CDK2-cyclin E activity
        promotes S-phase entry in large part by phosphorylating RB, enabling E2F
        transcriptional activation" (kasirzadeh2024targetingcdk2to). The IBA
        annotation is at the right level of specificity.
      supported_by:
        - reference_id: PMID:15838514
          supporting_text: >-
            Cyclin E-Cdk2 has long been considered an essential and master regulator of
            progression through G1 phase of the cell cycle
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for nuclear localization, consistent with the IBA and IDA
        annotations for the same term.
      action: ACCEPT
      reason: >-
        Redundant with IBA and IDA annotations but not wrong. Nuclear localization
        is well established for cyclin E1.
  - term:
      id: GO:0051301
      label: cell division
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation from UniProt keyword mapping. Cell division is a broad term
        that encompasses the G1/S transition role of cyclin E1.
      action: ACCEPT
      reason: >-
        While broader than the more specific G1/S transition annotations, this IEA
        is not wrong. Cyclin E1 is clearly involved in cell division. The UniProt
        record includes "Cell cycle; Cell division" as keywords.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10330164
    review:
      summary: >-
        Interaction with p300 coactivator. PMID:10330164 shows cyclin E-Cdk2 binds
        to the COOH-terminal region of p300, though this is described as a complex
        interaction (cyclin E-Cdk2 rather than cyclin E alone).
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        The term "protein binding" is uninformative. The actual finding is a specific
        interaction of cyclin E-Cdk2 complex with the p300 coactivator. However,
        the GO guidelines discourage generic protein binding annotations.
      supported_by:
        - reference_id: PMID:10330164
          supporting_text: >-
            the COOH-terminal region of p300 binds to cyclin E-cyclin-dependent kinase 2
            (cyclin E-Cdk2) and TFIIB
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11533444
    review:
      summary: >-
        Interaction with FBXW7 (SCFFbw7) for phosphorylation-dependent ubiquitination.
        This is a well-characterized substrate-E3 ligase interaction.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        The term "protein binding" is uninformative. The actual interaction is between
        cyclin E and FBXW7 as part of SCF-mediated ubiquitination. This is better
        captured by other annotations related to cyclin E degradation.
      supported_by:
        - reference_id: PMID:11533444
          supporting_text: >-
            Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin
            ligase
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16223725
    review:
      summary: >-
        Interaction with PIN1 prolyl isomerase. PIN1 regulates cyclin E stability.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The actual finding is PIN1
        regulation of cyclin E stability.
      supported_by:
        - reference_id: PMID:16223725
          supporting_text: >-
            The loss of PIN1 deregulates cyclin E and sensitizes mouse embryo fibroblasts
            to genomic instability
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16431923
    review:
      summary: >-
        Interaction with SARS-CoV nucleocapsid protein, which inhibits cyclin-CDK
        activity. This is a viral pathogen interaction, not a core function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The interaction is with a viral
        protein (SARS-CoV nucleocapsid) and represents pathogen interference with
        cell cycle, not a core function of cyclin E1.
      supported_by:
        - reference_id: PMID:16431923
          supporting_text: >-
            The nucleocapsid protein of severe acute respiratory syndrome-coronavirus
            inhibits the activity of cyclin-cyclin-dependent kinase complex and blocks
            S phase progression in mammalian cells
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16504183
    review:
      summary: >-
        Interaction with FOXM1c transcription factor, regulated by Cyclin E/CDK2.
        UniProt lists FOXM1 as an interaction partner.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The actual finding is regulation
        of FOXM1c by cyclin E/CDK2 complex phosphorylation.
      supported_by:
        - reference_id: PMID:16504183
          supporting_text: >-
            Regulation of the transcription factor FOXM1c by Cyclin E/CDK2
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16721056
    review:
      summary: >-
        Interaction with AKAP95 (A-kinase anchoring protein). G1/S cyclins interact
        with PKA regulatory subunit via AKAP95.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. UniProt lists AKAP8 as an
        interaction partner.
      supported_by:
        - reference_id: PMID:16721056
          supporting_text: >-
            G1/S Cyclins interact with regulatory subunit of PKA via A-kinase anchoring
            protein, AKAP95
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16765349
    review:
      summary: >-
        Interaction with p21 (CDKN1A) in retinoid-induced apoptosis. p21 is a
        well-known CDK inhibitor that forms complexes with cyclin E/CDK2.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The cyclin E-CDK2-p21 interaction
        is a core regulatory mechanism but should be annotated more specifically.
        UniProt lists CDKN1A with 11 experiments.
      supported_by:
        - reference_id: PMID:16765349
          supporting_text: >-
            Increased p21 expression and complex formation with cyclin E/CDK2 in
            retinoid-induced pre-B lymphoma cell apoptosis
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17254966
    review:
      summary: >-
        Interaction with p27Kip1 (CDKN1B). This is a key CDK inhibitor that
        regulates cyclin E-CDK2 activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The cyclin E-CDK2-p27 interaction
        is well characterized. UniProt lists CDKN1B with 12 experiments.
      supported_by:
        - reference_id: PMID:17254966
          supporting_text: >-
            Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by
            oncogenic tyrosine kinases
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17254967
    review:
      summary: >-
        Another study on p27-cyclin E-Cdk2 interaction, showing Src-dependent
        phosphorylation of p27 regulates inhibition of cyclin E-Cdk2.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. This is the same well-characterized
        p27-cyclin E-CDK2 interaction.
      supported_by:
        - reference_id: PMID:17254967
          supporting_text: >-
            p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17525332
    review:
      summary: >-
        Large-scale ATM/ATR substrate analysis. This is a high-throughput study
        identifying proteins in DNA damage response networks, not a focused study
        on cyclin E function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a high-throughput study. Does not provide
        specific information about cyclin E1 function.
      supported_by:
        - reference_id: PMID:17525332
          supporting_text: >-
            ATM and ATR substrate analysis reveals extensive protein networks responsive
            to DNA damage
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19470470
    review:
      summary: >-
        Study on RSK1-p27Kip1 phosphorylation. Cyclin E is mentioned as a binding
        partner of p27 but the study focuses on RSK1 function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The study focuses on RSK1
        regulation of p27, with cyclin E as a known interactor.
      supported_by:
        - reference_id: PMID:19470470
          supporting_text: >-
            RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and
            increase cell motility
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21092281
    review:
      summary: >-
        HTLV-I p30 decreases cyclin E-CDK2 interactions. This is a viral
        interference study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. This describes viral pathogen
        interference with cyclin E-CDK2, not a core function.
      supported_by:
        - reference_id: PMID:21092281
          supporting_text: >-
            HTLV-I p30 inhibits multiple S phase entry checkpoints, decreases cyclin
            E-CDK2 interactions and delays cell cycle progression
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21952639
    review:
      summary: >-
        Interaction with UHRF2 (NIRF), which ubiquitinates cyclin E1. UniProt
        confirms this interaction with 4 experiments.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The actual interaction is a
        substrate-E3 ligase relationship where UHRF2 ubiquitinates cyclin E1.
        UniProt states "Interacts directly with UHRF2; the interaction ubiquitinates
        CCNE1."
      supported_by:
        - reference_id: PMID:21952639
          supporting_text: >-
            the ubiquitin ligase NIRF (also known as UHRF2), which induces G1 arrest,
            interacts with multiple cell cycle proteins including cyclins (A2, B1, D1
            and E1), p53 and pRB, and ubiquitinates cyclins D1 and E1
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21988832
    review:
      summary: >-
        High-throughput protein interaction study of the human liver. Not a focused
        study on cyclin E1 function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a large-scale interactome study. Uninformative
        for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:21988832
          supporting_text: >-
            Toward an understanding of the protein interaction network of the human liver
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23455922
    review:
      summary: >-
        Large-scale AP-MS reproducibility study. Not a focused study on cyclin E1.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a high-throughput methods study. Uninformative
        for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:23455922
          supporting_text: >-
            Interlaboratory reproducibility of large-scale human protein-complex analysis
            by standardized AP-MS
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23602568
    review:
      summary: >-
        CMGC kinase group interactome study. CDK2 is a CMGC kinase, so cyclin E1
        would be identified as an interactor.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a kinase interactome study. The cyclin E-CDK2
        interaction is already well captured by more specific annotations.
      supported_by:
        - reference_id: PMID:23602568
          supporting_text: >-
            The protein interaction landscape of the human CMGC kinase group
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23853094
    review:
      summary: >-
        Foxp3 stability regulation by CDK2. The study shows CDK2 phosphorylates
        Foxp3, with cyclin E as the activating partner.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The actual biology is CDK2
        phosphorylation of Foxp3, where cyclin E1 is the activating cyclin partner.
      supported_by:
        - reference_id: PMID:23853094
          supporting_text: >-
            Foxp3 protein stability is regulated by cyclin-dependent kinase 2
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24358021
    review:
      summary: >-
        SCML2 binding to CDK/CYCLIN/p21 complexes. Cyclin E is one of the cyclins
        in such complexes.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The study describes SCML2
        modulating CDK/cyclin/p21 complexes, with cyclin E as one component.
      supported_by:
        - reference_id: PMID:24358021
          supporting_text: >-
            Polycomb protein SCML2 regulates the cell cycle by binding and modulating
            CDK/CYCLIN/p21 complexes
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25241761
    review:
      summary: >-
        In situ proximity ligation assay (PLA) study for profiling endogenous
        protein-protein interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a methods-focused study. Uninformative for
        cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:25241761
          supporting_text: >-
            Using an in situ proximity ligation assay to systematically profile
            endogenous protein-protein interactions in a pathway network
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25852190
    review:
      summary: >-
        Kinase network analysis in TRAIL-induced apoptosis. High-throughput study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a high-throughput network analysis study.
        Uninformative for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:25852190
          supporting_text: >-
            Integrative analysis of kinase networks in TRAIL-induced apoptosis provides
            a source of potential targets for combination therapy
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >-
        Large-scale human interactome architecture study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a large-scale interactome study. Uninformative
        for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: >-
            Architecture of the human interactome defines protein communities and disease
            networks
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        Binary protein interactome reference map.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a large-scale interactome mapping study.
        Uninformative for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: >-
            A reference map of the human binary protein interactome
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        Dual proteome-scale interactome study showing cell-specific remodeling.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a large-scale interactome study. Uninformative
        for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: >-
            Dual proteome-scale networks reveal cell-specific remodeling of the human
            interactome
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:34591612
    review:
      summary: >-
        Protein interaction landscape of breast cancer.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a tissue-specific interactome study.
        Uninformative for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:34591612
          supporting_text: >-
            A protein interaction landscape of breast cancer
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: >-
        OpenCell endogenous tagging and cartography study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a large-scale cellular organization study.
        Uninformative for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: >-
            OpenCell: Endogenous tagging for the cartography of human cellular
            organization
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35512704
    review:
      summary: >-
        Mutation-directed neo-protein-protein interactions in cancer.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a high-throughput cancer study. Uninformative
        for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:35512704
          supporting_text: >-
            Systematic discovery of mutation-directed neo-protein-protein interactions
            in cancer
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: >-
        Multimodal cell maps study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding from a large-scale cellular mapping study.
        Uninformative for cyclin E1 functional annotation.
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: >-
            Multimodal cell maps as a foundation for structural and functional genomics
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8553588
    review:
      summary: >-
        HPV E7 oncoproteins bind cyclin E in a complex with CDK2 and p107. This
        represents viral oncogene interaction with the cyclin E-CDK2 complex.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The actual finding involves viral
        E7 oncoprotein binding to cyclin E-CDK2-p107 complexes, which is a pathogen
        interaction, not a core function.
      supported_by:
        - reference_id: PMID:8553588
          supporting_text: >-
            Human papillomavirus E7 oncoproteins bind a single form of cyclin E in a
            complex with cdk2 and p107
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8756624
    review:
      summary: >-
        Cyclin-binding motifs essential for p21CIP1 function. This demonstrates the
        p21-cyclin E interaction is functionally important.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The study reveals specific
        cyclin-binding motifs in p21, but the annotation should be more specific
        than "protein binding."
      supported_by:
        - reference_id: PMID:8756624
          supporting_text: >-
            Cyclin-binding motifs are essential for the function of p21CIP1
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9840943
    review:
      summary: >-
        Cyclin E2 discovery paper that also characterizes cyclin E1 interactions with
        CDK2 and CDK3.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The CDK2 interaction is already
        captured by the more specific cyclin E1-CDK2 complex annotation
        (GO:0097134).
      supported_by:
        - reference_id: PMID:9840943
          supporting_text: >-
            Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and CDK3,
            is induced by viral oncoproteins
  - term:
      id: GO:0000307
      label: cyclin-dependent protein kinase holoenzyme complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for CDK holoenzyme complex membership. This is a more general
        parent of cyclin E1-CDK2 complex (GO:0097134).
      action: ACCEPT
      reason: >-
        While more general than GO:0097134 (cyclin E1-CDK2 complex), this IEA
        annotation is not wrong. Cyclin E1 is indeed a component of a
        cyclin-dependent protein kinase holoenzyme complex (the CDK2 holoenzyme).
        It is acceptable for IEA annotations to be broader.
  - term:
      id: GO:0016301
      label: kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation attributing kinase activity to cyclin E1. However, cyclin E1
        is NOT a kinase; it is a regulatory subunit that activates CDK2.
      action: REMOVE
      reason: >-
        Cyclin E1 does not have kinase activity itself. It is a non-enzymatic
        regulatory subunit that binds and activates CDK2. PMID:8207080 confirms
        "Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2."
        The kinase activity belongs to CDK2, not cyclin E1. The correct MF annotation
        is GO:0016538 (cyclin-dependent protein serine/threonine kinase regulator
        activity), which is already annotated. This IEA annotation is incorrect and
        should be removed.
      supported_by:
        - reference_id: PMID:8207080
          supporting_text: >-
            Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2,
            which is activated shortly before S-phase entry
  - term:
      id: GO:0016538
      label: cyclin-dependent protein serine/threonine kinase regulator activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation consistent with the IBA annotation for the same term.
        This is the correct molecular function for cyclin E1.
      action: ACCEPT
      reason: >-
        Consistent with the IBA annotation. This is the defining molecular function
        of cyclin E1 as a CDK2 regulatory subunit.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for protein kinase binding. Cyclin E1 does bind CDK2 (a
        protein kinase), so this is technically correct but vague.
      action: ACCEPT
      reason: >-
        Cyclin E1 binds CDK2, which is a protein kinase. UniProt states "Interacts
        with CDK2 protein kinase to form a serine/threonine kinase holoenzyme
        complex" (PMID:15660127). While more informative terms exist (GO:0016538),
        this IEA annotation is not incorrect and can be retained as a broader term.
  - term:
      id: GO:0097134
      label: cyclin E1-CDK2 complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation consistent with IBA annotation for the same term.
      action: ACCEPT
      reason: >-
        Consistent with the IBA annotation. Cyclin E1 is a defining component of
        the cyclin E1-CDK2 complex (ComplexPortal CPX-2015).
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        IDA annotation from HPA immunofluorescence data showing nucleoplasmic
        localization.
      action: ACCEPT
      reason: >-
        Nucleoplasmic localization is consistent with cyclin E1 being a nuclear
        protein that functions in cell cycle regulation within the nucleus.
        This is supported by multiple lines of evidence.
  - term:
      id: GO:0000082
      label: G1/S transition of mitotic cell cycle
    evidence_type: NAS
    original_reference_id: PMID:15838514
    review:
      summary: >-
        NAS annotation from a review article on cyclin E in normal and neoplastic
        cell cycles. Confirms the core function of cyclin E1 in G1/S transition.
      action: ACCEPT
      reason: >-
        Core function annotation supported by review literature. PMID:15838514
        states "Cyclin E-Cdk2 has long been considered an essential and master
        regulator of progression through G1 phase of the cell cycle."
      supported_by:
        - reference_id: PMID:15838514
          supporting_text: >-
            Cyclin E-Cdk2 has long been considered an essential and master regulator of
            progression through G1 phase of the cell cycle
  - term:
      id: GO:0000082
      label: G1/S transition of mitotic cell cycle
    evidence_type: IMP
    original_reference_id: PMID:23083510
    review:
      summary: >-
        IMP annotation from a study showing miR-16 targets cyclin E1 to inhibit
        mesenchymal stem cell proliferation and induce cell cycle arrest. Cyclin E1
        knockdown/downregulation caused cell cycle arrest, supporting its role in
        G1/S transition.
      action: ACCEPT
      reason: >-
        The study shows that miR-16 targets cyclin E1, and over-expression of
        miR-16 "inhibited the proliferation and migration of decidua-derived
        mesenchymal stem cells and induced cell-cycle arrest by targeting cyclin E1"
        (PMID:23083510). This supports cyclin E1 involvement in G1/S transition.
      supported_by:
        - reference_id: PMID:23083510
          supporting_text: >-
            over-expressed miR-16 inhibited the proliferation and migration of
            decidua-derived mesenchymal stem cells and induced cell-cycle arrest by
            targeting cyclin E1
  - term:
      id: GO:1902462
      label: positive regulation of mesenchymal stem cell proliferation
    evidence_type: IMP
    original_reference_id: PMID:23083510
    review:
      summary: >-
        IMP annotation from miR-16 study in pre-eclampsia. While cyclin E1 promotes
        proliferation of mesenchymal stem cells (shown by miR-16 targeting), this is
        a very specific biological context (decidual MSCs in pre-eclampsia) rather
        than a core function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cyclin E1 does promote proliferation in MSCs as shown by the miR-16 study,
        but this is a pleiotropic effect of its general cell cycle role in a
        specific cell type context, not a core evolved function. The annotation is
        technically supported but represents a context-specific manifestation.
      supported_by:
        - reference_id: PMID:23083510
          supporting_text: >-
            over-expressed miR-16 inhibited the proliferation and migration of
            decidua-derived mesenchymal stem cells and induced cell-cycle arrest by
            targeting cyclin E1
  - term:
      id: GO:0000082
      label: G1/S transition of mitotic cell cycle
    evidence_type: IMP
    original_reference_id: PMID:25732226
    review:
      summary: >-
        IMP annotation from study showing miR-30c-2-3p targets CCNE1 in breast
        cancer cells. Inhibition of CCNE1 phenocopied effects on cell proliferation.
      action: ACCEPT
      reason: >-
        The study confirms that CCNE1 downregulation affects cell cycle progression.
        "inhibition of CCNE1 phenocopied the effects on cell proliferation"
        (PMID:25732226). Supports G1/S transition role.
      supported_by:
        - reference_id: PMID:25732226
          supporting_text: >-
            inhibition of CCNE1 phenocopied the effects on cell proliferation
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21540187
    review:
      summary: >-
        Interaction with INCA1 (inhibitor of CDK interacting with cyclin A1).
        UniProt confirms "Interacts with INCA1" (PMID:21540187).
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The actual interaction is between
        cyclin E1 and INCA1, a CDK inhibitor. UniProt confirms this interaction.
      supported_by:
        - reference_id: PMID:21540187
          supporting_text: >-
            we identified INCA1 as an interaction partner and a substrate of cyclin A1
            in complex with CDK2
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:19942931
    review:
      summary: >-
        Nuclear localization of cyclin E1 observed in trophoblast cells. The study
        shows Mtd-L colocalizes with cyclin E1 in the nuclear compartment.
      action: ACCEPT
      reason: >-
        Nuclear localization confirmed by immunofluorescence in proliferating
        trophoblast cells. "Mtd expression in proliferating cells colocalized with
        cyclin E1, a G(1)/S phase cell cycle regulator" (PMID:19942931). Consistent
        with UniProt annotation.
      supported_by:
        - reference_id: PMID:19942931
          supporting_text: >-
            Mtd expression in proliferating cells colocalized with cyclin E1, a G(1)/S
            phase cell cycle regulator
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17434132
    review:
      summary: >-
        Structural study of Fbw7-Skp1-cyclin E complex. Demonstrates the molecular
        basis for cyclin E recognition by SCF-FBXW7 for ubiquitin-mediated
        degradation. This is a well-characterized interaction.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The actual finding is the structural
        basis for FBXW7 recognition of phosphorylated cyclin E degrons. This
        interaction is critical for cyclin E turnover but "protein binding" does not
        capture the functional significance.
      supported_by:
        - reference_id: PMID:17434132
          supporting_text: >-
            Cyclin E degradation is triggered by multisite phosphorylation, which
            induces binding to the SCF(Fbw7) ubiquitin ligase complex
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-187520
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasmic localization, from the Cyclin
        E/A:Cdk2-mediated phosphorylation of p27/p21 reaction.
      action: ACCEPT
      reason: >-
        Cyclin E-CDK2 mediates phosphorylation of p27/p21 in the nucleoplasm as
        part of the Skp2-mediated degradation pathway. Consistent with nuclear
        function.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-187552
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from binding of phospho-p27/p21
        to SCF(Skp2):Cks1 complex.
      action: ACCEPT
      reason: >-
        Consistent with established nucleoplasmic function of cyclin E-CDK2 complex.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-187574
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from degradation of ubiquitinated
        p27/p21 by 26S proteasome.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization during cell cycle regulation.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-187575
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from ubiquitination of
        phospho-p27/p21.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization during cell cycle regulation.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-188350
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from CAK-mediated phosphorylation
        of Cyclin E:Cdk2.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization during cell cycle regulation.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-188386
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from association of Rb with
        Cyclin E:Cdk2 complexes.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization for RB1 phosphorylation by
        cyclin E-CDK2.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-188390
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from Cyclin E:CDK2-mediated
        phosphorylation of RB1.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization for the core function of
        RB1 phosphorylation.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-69005
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from Cdc6 phosphorylation by CDK.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization. Cdc6 phosphorylation by
        cyclin E-CDK2 is part of DNA replication licensing.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-69195
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from phosphorylation of Cyclin
        E:CDK2 complexes by WEE1.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization during cell cycle checkpoint
        regulation.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-69199
    review:
      summary: >-
        Reactome TAS annotation for nucleoplasm, from dephosphorylation of Cyclin
        E:Cdk2 complexes by Cdc25A.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization during cell cycle regulation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-157906
    review:
      summary: >-
        Reactome TAS annotation for cytosol, from translocation of Cyclin E:Cdk2
        complex to the nucleus. Cyclin E-CDK2 is present in the cytosol before
        nuclear translocation.
      action: ACCEPT
      reason: >-
        Cyclin E-CDK2 complexes form in the cytosol before translocation to the
        nucleus. The Reactome reaction R-HSA-157906 specifically describes this
        translocation, implying cytosolic presence.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-69191
    review:
      summary: >-
        Reactome TAS annotation for cytosol, from formation of Cyclin E:Cdk2
        complexes.
      action: ACCEPT
      reason: >-
        Cyclin E-CDK2 complex formation occurs in the cytosol. Consistent with
        known biology of cyclin-CDK complex assembly.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8961846
    review:
      summary: >-
        Reactome TAS annotation for cytosol, from CCNE1 gene transcription
        stimulated by E2F1. This annotation seems to be about the gene product
        being present in cytosol in the context of its transcriptional regulation.
      action: ACCEPT
      reason: >-
        While the Reactome reaction is about transcriptional regulation, cyclin E1
        protein is synthesized in the cytosol. Consistent with cytoplasmic
        localization evidence.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9706390
    review:
      summary: >-
        Reactome TAS annotation for cytosol from RHOBTB3 interaction at trans-Golgi
        network. This is a less well-characterized interaction.
      action: ACCEPT
      reason: >-
        While the RHOBTB3 interaction context is less well characterized for cyclin
        E1, cytosolic presence is consistent with known nucleocytoplasmic shuttling
        of cyclin E.
  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: IMP
    original_reference_id: PMID:10500095
    review:
      summary: >-
        PMID:10500095 describes Cullin-3 targeting cyclin E for ubiquitination. The
        paper discusses cyclin E phosphorylation as a signal for degradation, and
        cyclin E-CDK2 complex kinase activity, but cyclin E itself does not catalyze
        phosphorylation. Cyclin E1 is a regulatory subunit, not a kinase.
      action: MODIFY
      reason: >-
        Cyclin E1 does not catalyze protein phosphorylation itself. It is a
        non-enzymatic regulatory subunit that activates CDK2. The annotation should
        be modified to reflect that cyclin E1 regulates protein kinase activity
        rather than directly performing phosphorylation. PMID:10500095 discusses
        "cyclin E-Cdk2 complexes" where CDK2 is the catalytic subunit. The paper
        actually focuses on "Cyclin E is an unstable protein that is degraded in a
        ubiquitin- and proteasome-dependent pathway."
      proposed_replacement_terms:
        - id: GO:0045859
          label: regulation of protein kinase activity
      supported_by:
        - reference_id: PMID:10500095
          supporting_text: >-
            Cyclin E is an unstable protein that is degraded in a ubiquitin- and
            proteasome- dependent pathway
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16109376
    review:
      summary: >-
        PMID:16109376 is about the bromodomain protein Brd4 and P-TEFb, not directly
        about cyclin E1. Brd4 interacts with cyclinT1 and Cdk9. The reference
        appears questionable for a CCNE1 nuclear localization annotation, as the
        paper primarily concerns cyclinT1/Cdk9. However, nuclear localization of
        cyclin E1 is well established by multiple other lines of evidence,
        including UniProt annotation with PMID:7739542 and IDA from PMID:19942931.
      action: ACCEPT
      reason: >-
        Although the specific reference PMID:16109376 may be a curatorial error
        (the paper focuses on Brd4/P-TEFb/cyclinT1/Cdk9 rather than cyclin E1),
        the nuclear localization of CCNE1 itself is unambiguously established.
        UniProt states "SUBCELLULAR LOCATION: Nucleus" with experimental evidence,
        and multiple other IDA annotations confirm nuclear localization
        (PMID:19942931). The annotation conclusion is correct even if the cited
        reference is questionable.
      supported_by:
        - reference_id: PMID:16109376
          supporting_text: >-
            Proteomic analysis revealed that Brd4 interacts with cyclinT1 and Cdk9 that
            constitutes core positive transcription elongation factor b (P-TEFb)
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9891079
    review:
      summary: >-
        Interaction with BAF155 and BRG1, components of the SWI-SNF chromatin
        remodeling complex. Cyclin E associates with these components and modulates
        BRG1-induced growth arrest.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic protein binding is uninformative. The actual finding is a specific
        interaction between cyclin E and SWI-SNF complex components (BAF155, BRG1)
        that may modulate chromatin remodeling during cell cycle progression.
      supported_by:
        - reference_id: PMID:9891079
          supporting_text: >-
            BRG1 and BAF155, mammalian homologs of yeast SWI2 and SWI3, respectively,
            are found in cyclin E complexes and are phosphorylated by cyclin
            E-associated kinase activity
  - term:
      id: GO:0000082
      label: G1/S transition of mitotic cell cycle
    evidence_type: NAS
    original_reference_id: PMID:8207080
    review:
      summary: >-
        NAS annotation from the alternative splicing paper. The paper establishes
        cyclin E as a G1 cyclin that activates CDK2 for S-phase entry.
      action: ACCEPT
      reason: >-
        PMID:8207080 confirms "Cyclin E is a regulatory subunit of the cdc2-related
        protein kinase cdk2, which is activated shortly before S-phase entry, thus
        defining it as a G1 cyclin." Core function annotation.
      supported_by:
        - reference_id: PMID:8207080
          supporting_text: >-
            Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2,
            which is activated shortly before S-phase entry, thus defining it as a G1
            cyclin
core_functions:
  - description: >-
      Cyclin E1 functions as a regulatory subunit that binds and activates CDK2
      (cyclin-dependent kinase 2), forming the cyclin E1-CDK2 holoenzyme complex.
      The cyclin E1-CDK2 complex phosphorylates RB1, releasing E2F transcription
      factors to activate S-phase gene expression, thereby driving the G1/S
      transition of the mitotic cell cycle.
    molecular_function:
      id: GO:0016538
      label: cyclin-dependent protein serine/threonine kinase regulator activity
    directly_involved_in:
      - id: GO:1900087
        label: positive regulation of G1/S transition of mitotic cell cycle
    locations:
      - id: GO:0005654
        label: nucleoplasm
    in_complex:
      id: GO:0097134
      label: cyclin E1-CDK2 complex
    supported_by:
      - reference_id: PMID:15838514
        supporting_text: >-
          Cyclin E-Cdk2 has long been considered an essential and master regulator of
          progression through G1 phase of the cell cycle
      - reference_id: PMID:8207080
        supporting_text: >-
          Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2,
          which is activated shortly before S-phase entry, thus defining it as a G1
          cyclin
references:
  - 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:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data
      to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10330164
    title: Specificity of cyclin E-Cdk2, TFIIB, and E1A interactions with a common
      domain of the p300 coactivator.
    findings: []
  - id: PMID:10500095
    title: Cullin-3 targets cyclin E for ubiquitination and controls S phase in
      mammalian cells.
    findings: []
  - id: PMID:11533444
    title: Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7
      ubiquitin ligase.
    findings: []
  - id: PMID:15838514
    title: Cyclin E in normal and neoplastic cell cycles.
    findings: []
  - id: PMID:16109376
    title: The bromodomain protein Brd4 is a positive regulatory component of P-TEFb
      and stimulates RNA polymerase II-dependent transcription.
    findings: []
  - id: PMID:16223725
    title: The loss of PIN1 deregulates cyclin E and sensitizes mouse embryo
      fibroblasts to genomic instability.
    findings: []
  - id: PMID:16431923
    title: The nucleocapsid protein of severe acute respiratory
      syndrome-coronavirus inhibits the activity of cyclin-cyclin-dependent kinase
      complex and blocks S phase progression in mammalian cells.
    findings: []
  - id: PMID:16504183
    title: Regulation of the transcription factor FOXM1c by Cyclin E/CDK2.
    findings: []
  - id: PMID:16721056
    title: G1/S Cyclins interact with regulatory subunit of PKA via A-kinase
      anchoring protein, AKAP95.
    findings: []
  - id: PMID:16765349
    title: Increased p21 expression and complex formation with cyclin E/CDK2 in
      retinoid-induced pre-B lymphoma cell apoptosis.
    findings: []
  - id: PMID:17254966
    title: Cdk-inhibitory activity and stability of p27Kip1 are directly regulated
      by oncogenic tyrosine kinases.
    findings: []
  - id: PMID:17254967
    title: p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.
    findings: []
  - id: PMID:17434132
    title: 'Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated
      substrate recognition by SCF ubiquitin ligases.'
    findings: []
  - id: PMID:17525332
    title: ATM and ATR substrate analysis reveals extensive protein networks
      responsive to DNA damage.
    findings: []
  - id: PMID:19470470
    title: RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition
      and increase cell motility.
    findings: []
  - id: PMID:19942931
    title: 'Mtd/Bok takes a swing: proapoptotic Mtd/Bok regulates trophoblast cell
      proliferation during human placental development and in preeclampsia.'
    findings: []
  - id: PMID:21092281
    title: HTLV-I p30 inhibits multiple S phase entry checkpoints, decreases cyclin
      E-CDK2 interactions and delays cell cycle progression.
    findings: []
  - id: PMID:21540187
    title: Inhibitor of cyclin-dependent kinase (CDK) interacting with cyclin A1
      (INCA1) regulates proliferation and is repressed by oncogenic signaling.
    findings: []
  - id: PMID:21952639
    title: NIRF constitutes a nodal point in the cell cycle network and is a
      candidate tumor suppressor.
    findings: []
  - id: PMID:21988832
    title: Toward an understanding of the protein interaction network of the human
      liver.
    findings: []
  - id: PMID:23083510
    title: miR-16 inhibits the proliferation and angiogenesis-regulating potential of
      mesenchymal stem cells in severe pre-eclampsia.
    findings: []
  - id: PMID:23455922
    title: Interlaboratory reproducibility of large-scale human protein-complex
      analysis by standardized AP-MS.
    findings: []
  - id: PMID:23602568
    title: The protein interaction landscape of the human CMGC kinase group.
    findings: []
  - id: PMID:23853094
    title: Foxp3 protein stability is regulated by cyclin-dependent kinase 2.
    findings: []
  - id: PMID:24358021
    title: Polycomb protein SCML2 regulates the cell cycle by binding and modulating
      CDK/CYCLIN/p21 complexes.
    findings: []
  - id: PMID:25241761
    title: Using an in situ proximity ligation assay to systematically profile
      endogenous protein-protein interactions in a pathway network.
    findings: []
  - id: PMID:25732226
    title: 'MicroRNA-30c-2-3p negatively regulates NF-κB signaling and cell cycle
      progression through downregulation of TRADD and CCNE1 in breast cancer.'
    findings: []
  - id: PMID:25852190
    title: Integrative analysis of kinase networks in TRAIL-induced apoptosis
      provides a source of potential targets for combination therapy.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human
      interactome.
    findings: []
  - id: PMID:34591612
    title: A protein interaction landscape of breast cancer.
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular
      organization.'
    findings: []
  - id: PMID:35512704
    title: Systematic discovery of mutation-directed neo-protein-protein interactions
      in cancer.
    findings: []
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional
      genomics.
    findings: []
  - id: PMID:8207080
    title: Alternative splicing of human cyclin E.
    findings: []
  - id: PMID:8553588
    title: Human papillomavirus E7 oncoproteins bind a single form of cyclin E in a
      complex with cdk2 and p107.
    findings: []
  - id: PMID:8756624
    title: Cyclin-binding motifs are essential for the function of p21CIP1.
    findings: []
  - id: PMID:9840943
    title: Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and
      CDK3, is induced by viral oncoproteins.
    findings: []
  - id: PMID:9891079
    title: 'Cyclin E associates with BAF155 and BRG1, components of the mammalian
      SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest.'
    findings: []
  - id: Reactome:R-HSA-157906
    title: Translocation of Cyclin E:Cdk2 complex to the nucleus
    findings: []
  - id: Reactome:R-HSA-187520
    title: Cyclin E/A:Cdk2-mediated  phosphorylation of p27/p21
    findings: []
  - id: Reactome:R-HSA-187552
    title: Binding of phospho-p27/p21:Cdk2:Cyclin E/A to the SCF(Skp2):Cks1 complex
    findings: []
  - id: Reactome:R-HSA-187574
    title: Degradation of ubiquitinated p27/p21 by the 26S proteasome
    findings: []
  - id: Reactome:R-HSA-187575
    title: Ubiquitination of phospho-p27/p21
    findings: []
  - id: Reactome:R-HSA-188350
    title: CAK-mediated phosphorylation of Cyclin E:Cdk2
    findings: []
  - id: Reactome:R-HSA-188386
    title: Association of Rb with Cyclin E:Cdk2 complexes
    findings: []
  - id: Reactome:R-HSA-188390
    title: Cyclin E:CDK2-mediated phosphorylation of RB1
    findings: []
  - id: Reactome:R-HSA-69005
    title: Cdc6 protein is phosphorylated by CDK
    findings: []
  - id: Reactome:R-HSA-69191
    title: Formation of Cyclin E:Cdk2 complexes
    findings: []
  - id: Reactome:R-HSA-69195
    title: Phosphorylation of Cyclin E:CDK2 complexes by WEE1
    findings: []
  - id: Reactome:R-HSA-69199
    title: Dephosphorylation of Cyclin E:Cdk2 complexes by Cdc25A
    findings: []
  - id: Reactome:R-HSA-8961846
    title: CCNE1 gene transcription is stimulated by E2F1
    findings: []
  - id: Reactome:R-HSA-9706390
    title: RHOBTB3 binds interacting proteins at trans-Golgi network
    findings: []