id: Q00535
gene_symbol: CDK5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CDK5 encodes a proline-directed serine/threonine kinase activated by CDK5R1/p35, CDK5R1/p25, and
  CDK5R2/p39 family regulators, with major functions in neuronal development, neurite and axon growth,
  cytoskeletal and dendritic-spine dynamics, synaptic vesicle cycling, synaptic plasticity, and
  p25-linked neurodegenerative apoptosis as a stress/disease context. Human CDK5 also regulates
  induced neuronal autophagy through phosphorylation of SH3GLB1/endophilin B1. Beyond the nervous
  system, CDK5 partners with cyclin B1 in proliferating cells and is active during mitosis, where it
  acts as a canonical CDK-cyclin kinase required for mitotic fidelity.
alternative_products:
- name: '1'
  id: Q00535-1
- name: 2 (CDK5-SV {ECO:0000303|PubMed:19693690})
  id: Q00535-2
  sequence_note: VSP_041948
existing_annotations:
- term:
    id: GO:0000307
    label: cyclin-dependent protein kinase holoenzyme complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: cyclin-dependent protein kinase holoenzyme complex is a supported CDK5 kinase-complex annotation.
    action: ACCEPT
    reason: CDK5 functions as a catalytic subunit in heterodimeric CDK5R-containing kinase complexes.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: cytoplasm is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0004693
    label: cyclin-dependent protein serine/threonine kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: cyclin-dependent protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:1901987
    label: regulation of cell cycle phase transition
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: regulation of cell cycle phase transition is a core CDK5 process. CDK5 was long classified as an atypical CDK with no direct cell-cycle role, but Zheng et al. 2024 (Nature) demonstrated that CDK5 is active during mitosis, partners with cyclin B1, and is required for mitotic fidelity - a direct, enzymatically-mediated function rather than over-propagation.
    action: ACCEPT
    reason: Experimentally established direct function- CDK5-cyclin B1 acts as a canonical CDK-cyclin complex that phosphorylates mitotic substrates to ensure mitotic fidelity (Zheng et al. 2024, PMID:39232161). This is a bona fide core CDK5 kinase function operating in proliferating cells via cyclin B1, complementary to (not subordinate to) its p35/p39-activated neuronal kinase role.
    supported_by:
    - reference_id: PMID:39232161
      supporting_text: CDK5 is active throughout mitosis
    - reference_id: PMID:39232161
      supporting_text: cyclin B1 is a mitotic co-factor of CDK5
    - reference_id: file:human/CDK5/CDK5-deep-research-falcon.md
      supporting_text: CDK5 can form a complex with cyclin B1 and regulate mitotic fidelity, challenging the traditional view that CDK5 has no cell cycle function
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
- term:
    id: GO:0007409
    label: axonogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: axonogenesis is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0048489
    label: synaptic vesicle transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: synaptic vesicle transport is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0051402
    label: neuron apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Keep neuron apoptotic process as a non-core p25-linked neurotoxicity/stress annotation rather than canonical core CDK5 neuronal kinase biology.
    action: KEEP_AS_NON_CORE
    reason: The strongest apoptosis evidence is pathological calpain cleavage of CDK5R1/p35 to p25, causing constitutive and mislocalized CDK5 activity in neurodegenerative stress models; this is not the core developmental/synaptic CDK5 function.
    supported_by:
    - reference_id: PMID:10604467
      supporting_text: p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease
    - reference_id: PMID:10604467
      supporting_text: p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis
    - reference_id: PMID:10604467
      supporting_text: cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: protein kinase activity is correct but too broad for CDK5.
    action: MODIFY
    reason: Replace the broad kinase parent with the more informative cyclin-dependent protein serine/threonine kinase activity term.
    proposed_replacement_terms:
    - id: GO:0004693
      label: cyclin-dependent protein serine/threonine kinase activity
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP binding is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: nucleus is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: cytoplasm is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: plasma membrane is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0007409
    label: axonogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: axonogenesis is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Accept postsynaptic density as a supported synaptic CDK5 localization.
    action: ACCEPT
    reason: UniProt gives a specific postsynaptic density localization by similarity, consistent with CDK5 synaptic substrate regulation.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Postsynaptic density
- term:
    id: GO:0030027
    label: lamellipodium
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Accept lamellipodium as a specific CDK5 cell-projection localization supported by UniProt.
    action: ACCEPT
    reason: The UniProt subcellular-location line explicitly includes lamellipodium in the cell-projection context.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Perikaryon. Cell projection, lamellipodium
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: growth cone is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Accept perikaryon as a specific CDK5 neuronal-cell-body localization supported by UniProt.
    action: ACCEPT
    reason: The UniProt subcellular-location line explicitly includes perikaryon.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Perikaryon. Cell projection, lamellipodium
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: synapse is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0051649
    label: establishment of localization in cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: establishment of localization in cell is a secondary or broad CDK5 process annotation.
    action: KEEP_AS_NON_CORE
    reason: The term reflects a true downstream or disease/stress context, but it is broader or less central than CDK5 kinase activity and neuronal/synaptic substrate regulation.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0051726
    label: regulation of cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: regulation of cell cycle is a core CDK5 process. Historically CDK5 was thought to lack a direct cell-cycle role; Zheng et al. 2024 (Nature) showed CDK5 is active during mitosis and, with cyclin B1, is required for mitotic fidelity, establishing this as a genuine direct function.
    action: ACCEPT
    reason: Experimentally established by the demonstration that CDK5 forms a functional CDK-cyclin complex with cyclin B1 and ensures mitotic fidelity (Zheng et al. 2024, PMID:39232161). Treated as a core CDK5 kinase function in proliferating cells, complementary to its p35/p39-activated neuronal/synaptic signaling.
    supported_by:
    - reference_id: PMID:39232161
      supporting_text: CDK5 is active throughout mitosis
    - reference_id: PMID:39232161
      supporting_text: cyclin B1 is a mitotic co-factor of CDK5
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Keep presynapse as non-core synaptic localization context.
    action: KEEP_AS_NON_CORE
    reason: The accessible UniProt text supports synapse broadly, but not presynapse specifically; the core localization should remain broader synapse/postsynaptic density/growth cone/neuron projection contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Synapse
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: Protein serine kinase activity is too narrow/incomplete for CDK5.
    action: MODIFY
    reason: CDK5 phosphorylates both serine and threonine residues, so protein serine/threonine kinase activity is the better molecular-function term.
    proposed_replacement_terms:
    - id: GO:0004674
      label: protein serine/threonine kinase activity
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14521924
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15689152
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15890360
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17078951
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20133653
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20559324
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21220307
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22078880
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23455922
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23543736
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23602568
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25852190
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107012
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30833792
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32812023
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591612
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35016035
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35063084
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0002039
    label: p53 binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: p53 binding is a specific substrate/regulator binding context, not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: This binding annotation is more specific than generic protein binding, but CDK5 should primarily be represented by kinase activity and substrate phosphorylation/regulation terms.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Interacts with P53/TP53 in neurons
- term:
    id: GO:0005176
    label: ErbB-2 class receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: ErbB-2 class receptor binding overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0016533
    label: protein kinase 5 complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: protein kinase 5 complex is a supported CDK5 kinase-complex annotation.
    action: ACCEPT
    reason: CDK5 functions as a catalytic subunit in heterodimeric CDK5R-containing kinase complexes.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0030175
    label: filopodium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Keep filopodium as non-core fine cell-projection localization context.
    action: KEEP_AS_NON_CORE
    reason: The accessible evidence supports CDK5 at cell projections and lamellipodia/growth cones, but not a specific filopodium localization as a core CDK5 compartment.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Perikaryon. Cell projection, lamellipodium
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: axon is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0030547
    label: signaling receptor inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: signaling receptor inhibitor activity overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0030549
    label: acetylcholine receptor activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: acetylcholine receptor activator activity overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0043125
    label: ErbB-3 class receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: ErbB-3 class receptor binding overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Hsp90 protein binding overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0051966
    label: regulation of synaptic transmission, glutamatergic
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: regulation of synaptic transmission, glutamatergic is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0061001
    label: regulation of dendritic spine morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: regulation of dendritic spine morphogenesis is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:1903076
    label: regulation of protein localization to plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: regulation of protein localization to plasma membrane is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0000307
    label: cyclin-dependent protein kinase holoenzyme complex
  evidence_type: IPI
  original_reference_id: PMID:16039528
  qualifier: part_of
  review:
    summary: cyclin-dependent protein kinase holoenzyme complex is a supported CDK5 kinase-complex annotation.
    action: ACCEPT
    reason: CDK5 functions as a catalytic subunit in heterodimeric CDK5R-containing kinase complexes.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0016533
    label: protein kinase 5 complex
  evidence_type: IPI
  original_reference_id: PMID:15689152
  qualifier: part_of
  review:
    summary: protein kinase 5 complex is a supported CDK5 kinase-complex annotation.
    action: ACCEPT
    reason: CDK5 functions as a catalytic subunit in heterodimeric CDK5R-containing kinase complexes.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0016533
    label: protein kinase 5 complex
  evidence_type: IPI
  original_reference_id: PMID:16039528
  qualifier: part_of
  review:
    summary: protein kinase 5 complex is a supported CDK5 kinase-complex annotation.
    action: ACCEPT
    reason: CDK5 functions as a catalytic subunit in heterodimeric CDK5R-containing kinase complexes.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: nucleoplasm is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: plasma membrane is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399944
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863007
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863011
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863014
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004693
    label: cyclin-dependent protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-180047
  qualifier: enables
  review:
    summary: cyclin-dependent protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:24607229
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0030547
    label: signaling receptor inhibitor activity
  evidence_type: IMP
  original_reference_id: PMID:24607229
  qualifier: enables
  review:
    summary: signaling receptor inhibitor activity overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0035255
    label: ionotropic glutamate receptor binding
  evidence_type: IPI
  original_reference_id: PMID:24607229
  qualifier: enables
  review:
    summary: ionotropic glutamate receptor binding is a specific substrate/regulator binding context, not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: This binding annotation is more specific than generic protein binding, but CDK5 should primarily be represented by kinase activity and substrate phosphorylation/regulation terms.
    supported_by:
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:12691662
  qualifier: located_in
  review:
    summary: nucleus is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:12691662
  qualifier: located_in
  review:
    summary: cytoplasm is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:17009320
  qualifier: located_in
  review:
    summary: plasma membrane is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Accept postsynaptic density as a supported synaptic CDK5 localization.
    action: ACCEPT
    reason: UniProt gives a specific postsynaptic density localization by similarity, consistent with CDK5 synaptic substrate regulation.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Postsynaptic density
- term:
    id: GO:0045202
    label: synapse
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: synapse is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0099533
    label: positive regulation of presynaptic cytosolic calcium concentration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: positive regulation of presynaptic cytosolic calcium concentration is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:1903234
    label: negative regulation of calcium ion-dependent exocytosis of neurotransmitter
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: acts_upstream_of_or_within
  review:
    summary: negative regulation of calcium ion-dependent exocytosis of neurotransmitter is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: PMID:17491008
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0030036
    label: actin cytoskeleton organization
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: actin cytoskeleton organization is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8090221
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: NAS
  original_reference_id: PMID:28386764
  qualifier: enables
  review:
    summary: tau protein binding is a specific substrate/regulator binding context, not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: This binding annotation is more specific than generic protein binding, but CDK5 should primarily be represented by kinase activity and substrate phosphorylation/regulation terms.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: MAPT/TAU, MAP2, MAP1B
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B)
- term:
    id: GO:0050321
    label: tau-protein kinase activity
  evidence_type: NAS
  original_reference_id: PMID:28386764
  qualifier: enables
  review:
    summary: tau-protein kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: MAPT/TAU, MAP2, MAP1B
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0016020
    label: membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: membrane is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: growth cone is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: neuron projection is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: NAS
  original_reference_id: PMID:28386764
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0051966
    label: regulation of synaptic transmission, glutamatergic
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: regulation of synaptic transmission, glutamatergic is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: cytoplasm is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: colocalizes_with
  review:
    summary: microtubule is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: PMID:17491008
      supporting_text: p35 binds directly to alpha/beta-tubulin and microtubules
    - reference_id: PMID:17491008
      supporting_text: Microtubule polymers but not the alpha/beta-tubulin heterodimer block p35 interaction with Cdk5
- term:
    id: GO:0008017
    label: microtubule binding
  evidence_type: TAS
  original_reference_id: PMID:17491008
  qualifier: enables
  negated: true
  review:
    summary: Microtubule binding is over-attributed to CDK5 itself.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited evidence supports microtubule binding by the p35/CDK5R1 activator and regulation of CDK5-p35 activity by microtubules, not direct CDK5 microtubule-binding as its molecular function.
    supported_by:
    - reference_id: PMID:17491008
      supporting_text: p35 binds directly to alpha/beta-tubulin and microtubules
    - reference_id: PMID:17491008
      supporting_text: Microtubule polymers but not the alpha/beta-tubulin heterodimer block p35 interaction with Cdk5
- term:
    id: GO:0000226
    label: microtubule cytoskeleton organization
  evidence_type: TAS
  original_reference_id: PMID:17491008
  qualifier: involved_in
  review:
    summary: microtubule cytoskeleton organization is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0031175
    label: neuron projection development
  evidence_type: TAS
  original_reference_id: PMID:17491008
  qualifier: involved_in
  review:
    summary: neuron projection development is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0048167
    label: regulation of synaptic plasticity
  evidence_type: TAS
  original_reference_id: PMID:24607229
  qualifier: involved_in
  review:
    summary: regulation of synaptic plasticity is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:1903076
    label: regulation of protein localization to plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: regulation of protein localization to plasma membrane is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:1904646
    label: cellular response to amyloid-beta
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: cellular response to amyloid-beta is a secondary or broad CDK5 process annotation.
    action: KEEP_AS_NON_CORE
    reason: The term reflects a true downstream or disease/stress context, but it is broader or less central than CDK5 kinase activity and neuronal/synaptic substrate regulation.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863014
  qualifier: located_in
  review:
    summary: nucleoplasm is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863587
  qualifier: located_in
  review:
    summary: nucleoplasm is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6805276
  qualifier: located_in
  review:
    summary: nucleoplasm is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: TAS
  original_reference_id: PMID:21499257
  qualifier: involved_in
  review:
    summary: Regulation of macroautophagy is a supported PN-relevant CDK5 substrate-specific process.
    action: ACCEPT
    reason: Human/neuron evidence shows CDK5 phosphorylates SH3GLB1/endophilin B1 and is required for induced autophagy in starved neurons and Parkinson disease models.
    supported_by:
    - reference_id: PMID:21499257
      supporting_text: unexpected role for Cdk5 in the regulation of induced autophagy in neurons
    - reference_id: PMID:21499257
      supporting_text: autophagy induction in starved neurons
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons
- term:
    id: GO:1903421
    label: regulation of synaptic vesicle recycling
  evidence_type: NAS
  original_reference_id: PMID:22745285
  qualifier: involved_in
  review:
    summary: regulation of synaptic vesicle recycling is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0045861
    label: negative regulation of proteolysis
  evidence_type: IMP
  original_reference_id: PMID:24548080
  qualifier: involved_in
  review:
    summary: negative regulation of proteolysis is a secondary or broad CDK5 process annotation.
    action: KEEP_AS_NON_CORE
    reason: The term reflects a true downstream or disease/stress context, but it is broader or less central than CDK5 kinase activity and neuronal/synaptic substrate regulation.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399944
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399951
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-9032945
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-180047
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863007
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863011
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863013
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8863587
  qualifier: located_in
  review:
    summary: cytosol is a broad or complex-context CDK5 localization.
    action: KEEP_AS_NON_CORE
    reason: This location is compatible with CDK5 biology but is less informative than CDK5 kinase-complex, synaptic, neuronal projection, and growth-cone contexts.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
- term:
    id: GO:0048167
    label: regulation of synaptic plasticity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: regulation of synaptic plasticity is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0001764
    label: neuron migration
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: neuron migration is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0007268
    label: chemical synaptic transmission
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: chemical synaptic transmission is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0007416
    label: synapse assembly
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: synapse assembly is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0016079
    label: synaptic vesicle exocytosis
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: synaptic vesicle exocytosis is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: neuron differentiation is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: regulation of apoptotic process is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0048167
    label: regulation of synaptic plasticity
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: regulation of synaptic plasticity is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0048488
    label: synaptic vesicle endocytosis
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: synaptic vesicle endocytosis is a core CDK5 synaptic process.
    action: ACCEPT
    reason: CDK5 phosphorylates synaptic release, endocytosis, and NMDAR-associated substrates and regulates synaptic plasticity/neurotransmission.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
    - reference_id: PMID:24607229
      supporting_text: controls the receptor's cell surface expression
    - reference_id: PMID:24607229
      supporting_text: serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5)
    - reference_id: PMID:24607229
      supporting_text: increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0048675
    label: axon extension
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: axon extension is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0048709
    label: oligodendrocyte differentiation
  evidence_type: IDA
  original_reference_id: PMID:18042622
  qualifier: involved_in
  review:
    summary: oligodendrocyte differentiation is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0051402
    label: neuron apoptotic process
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: Keep neuron apoptotic process as a non-core p25-linked neurotoxicity/stress annotation rather than canonical core CDK5 neuronal kinase biology.
    action: KEEP_AS_NON_CORE
    reason: The strongest apoptosis evidence is pathological calpain cleavage of CDK5R1/p35 to p25, causing constitutive and mislocalized CDK5 activity in neurodegenerative stress models; this is not the core developmental/synaptic CDK5 function.
    supported_by:
    - reference_id: PMID:10604467
      supporting_text: p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease
    - reference_id: PMID:10604467
      supporting_text: p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis
    - reference_id: PMID:10604467
      supporting_text: cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases
- term:
    id: GO:0051726
    label: regulation of cell cycle
  evidence_type: TAS
  original_reference_id: PMID:21473899
  qualifier: involved_in
  review:
    summary: regulation of cell cycle is a core CDK5 process. Historically CDK5 was thought to lack a direct cell-cycle role; Zheng et al. 2024 (Nature) showed CDK5 is active during mitosis and, with cyclin B1, is required for mitotic fidelity, establishing this as a genuine direct function.
    action: ACCEPT
    reason: Experimentally established by the demonstration that CDK5 forms a functional CDK-cyclin complex with cyclin B1 and ensures mitotic fidelity (Zheng et al. 2024, PMID:39232161). Treated as a core CDK5 kinase function in proliferating cells, complementary to its p35/p39-activated neuronal/synaptic signaling.
    supported_by:
    - reference_id: PMID:39232161
      supporting_text: CDK5 is active throughout mitosis
    - reference_id: PMID:39232161
      supporting_text: cyclin B1 is a mitotic co-factor of CDK5
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
- term:
    id: GO:0061001
    label: regulation of dendritic spine morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: regulation of dendritic spine morphogenesis is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:20357208
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:20357208
  qualifier: involved_in
  review:
    summary: negative regulation of DNA-templated transcription is a secondary or broad CDK5 process annotation.
    action: KEEP_AS_NON_CORE
    reason: The term reflects a true downstream or disease/stress context, but it is broader or less central than CDK5 kinase activity and neuronal/synaptic substrate regulation.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:21145489
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0005176
    label: ErbB-2 class receptor binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ErbB-2 class receptor binding overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12223541
  qualifier: enables
  review:
    summary: Generic protein binding does not describe CDK5 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific function is CDK5-regulated phosphorylation in CDK5R/p35-p25-p39 complexes and substrate-specific neuronal/autophagy signaling. Generic protein binding rows should not be treated as informative GO molecular-function annotations.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: nucleus is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: kinase activity is correct but too broad for CDK5.
    action: MODIFY
    reason: Replace the broad kinase parent with the more informative cyclin-dependent protein serine/threonine kinase activity term.
    proposed_replacement_terms:
    - id: GO:0004693
      label: cyclin-dependent protein serine/threonine kinase activity
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: neuron differentiation is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0030424
    label: axon
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: axon is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: dendrite is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0030549
    label: acetylcholine receptor activator activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: acetylcholine receptor activator activity overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0031175
    label: neuron projection development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: neuron projection development is part of core CDK5 neuronal kinase biology.
    action: ACCEPT
    reason: CDK5 regulates neuronal development, neurite/axon growth, cytoskeletal dynamics, synaptogenesis, oligodendrocyte differentiation, and neuronal survival/death.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: neuromuscular junction is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: neuronal cell body is a supported CDK5 localization/context.
    action: ACCEPT
    reason: The localization is consistent with CDK5 neuronal kinase function across cytoplasm, nucleus, membranes, synapses, growth cones, and neuronal projections.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm'
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:12691662}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:17009320}
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
    - reference_id: PMID:21473899
      supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
- term:
    id: GO:0043125
    label: ErbB-3 class receptor binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ErbB-3 class receptor binding overstates a downstream/regulatory interaction as a CDK5 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These transferred receptor/regulator-binding terms do not capture CDK5's catalytic function and are less defensible than kinase activity plus substrate-specific process annotations.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0043525
    label: positive regulation of neuron apoptotic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Keep positive regulation of neuron apoptotic process as a non-core p25-linked neurotoxicity/stress annotation rather than canonical core CDK5 neuronal kinase biology.
    action: KEEP_AS_NON_CORE
    reason: The strongest apoptosis evidence is pathological calpain cleavage of CDK5R1/p35 to p25, causing constitutive and mislocalized CDK5 activity in neurodegenerative stress models; this is not the core developmental/synaptic CDK5 function.
    supported_by:
    - reference_id: PMID:10604467
      supporting_text: p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease
    - reference_id: PMID:10604467
      supporting_text: p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis
    - reference_id: PMID:10604467
      supporting_text: cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases
- term:
    id: GO:0050321
    label: tau-protein kinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: tau-protein kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: MAPT/TAU, MAP2, MAP1B
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: TAS
  original_reference_id: PMID:1639063
  qualifier: enables
  review:
    summary: protein kinase activity is correct but too broad for CDK5.
    action: MODIFY
    reason: Replace the broad kinase parent with the more informative cyclin-dependent protein serine/threonine kinase activity term.
    proposed_replacement_terms:
    - id: GO:0004693
      label: cyclin-dependent protein serine/threonine kinase activity
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: TAS
  original_reference_id: PMID:7834371
  qualifier: enables
  review:
    summary: protein kinase activity is correct but too broad for CDK5.
    action: MODIFY
    reason: Replace the broad kinase parent with the more informative cyclin-dependent protein serine/threonine kinase activity term.
    proposed_replacement_terms:
    - id: GO:0004693
      label: cyclin-dependent protein serine/threonine kinase activity
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: PMID:1639063
  qualifier: enables
  review:
    summary: protein serine/threonine kinase activity is a core CDK5 molecular function.
    action: ACCEPT
    reason: CDK5 is a CDK-family proline-directed serine/threonine protein kinase that uses ATP and is activated in CDK5R-containing kinase complexes; tau/MAPT and other neuronal proteins are established substrates.
    supported_by:
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Proline-directed serine/threonine-protein kinase
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
    - reference_id: file:human/CDK5/CDK5-uniprot.txt
      supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  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: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: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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:39232161
  title: CDK5-cyclin B1 regulates mitotic fidelity.
  findings:
  - statement: CDK5, long classified as an atypical CDK without a direct cell-cycle role, is active during mitosis and partners with cyclin B1 (not only its neuronal p35/p39 activators) to maintain mitotic fidelity, validating CDK5 cell-cycle-regulation annotations as a genuine extra-neuronal function.
    supporting_text: CDK5 is active throughout mitosis
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed/PMC-verified (PMID:39232161, Nature 2024). Establishes a bona fide, direct mitotic role for CDK5 via cyclin B1 (a canonical CDK-cyclin complex ensuring mitotic fidelity); basis for treating regulation of cell cycle / cell cycle phase transition as a core CDK5 function alongside its neuronal kinase biology.
- id: file:human/CDK5/CDK5-deep-research-falcon.md
  title: Falcon deep research report for CDK5
  findings:
  - statement: Falcon deep research corroborates the existing CDK5 review (p35/p39 activation, p25 hyperactivation, tau/synaptic/cytoskeletal substrates, neurodegeneration) and surfaces the 2024 Nature CDK5-cyclin B1 mitotic-fidelity finding plus additional substrate-specific roles (Drp1 mitochondrial fission, CLOCK/PER2 circadian, PRMT1-mTORC1).
    supporting_text: CDK5 can form a complex with cyclin B1 and regulate mitotic fidelity, challenging the traditional view that CDK5 has no cell cycle function
- id: PMID:12223541
  title: The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner.
  findings: []
- id: PMID:12691662
  title: Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis.
  findings: []
- id: PMID:14521924
  title: Apoptosis-associated tyrosine kinase is a Cdk5 activator p35 binding protein.
  findings: []
- id: PMID:15689152
  title: Mechanism of CDK5/p25 binding by CDK inhibitors.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports the CDK5/p25 kinase-complex 
      structure used for CDK5 complex and inhibitor-binding context, but it is 
      not the primary physiological-function evidence.
- id: PMID:15890360
  title: Molecular basis for the specificity of p27 toward cyclin-dependent kinases that regulate cell division.
  findings: []
- id: PMID:16039528
  title: Defining Cdk5 ligand chemical space with small molecule inhibitors of tau phosphorylation.
  findings: []
- id: PMID:1639063
  title: A family of human cdc2-related protein kinases.
  findings: []
- id: PMID:17009320
  title: cdk5 modulates beta- and delta-catenin/Pin1 interactions in neuronal cells.
  findings: []
- id: PMID:17078951
  title: PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.
  findings: []
- id: PMID:17491008
  title: Microtubule association of the neuronal p35 activator of Cdk5.
  findings:
  - statement: p35/CDK5R1, not necessarily CDK5 itself, binds microtubules and regulates CDK5-p35 activity.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports microtubule association of the p35 
      activator and regulation of CDK5-p35 activity; this cautions against 
      treating CDK5 itself as the direct microtubule-binding protein.
- id: PMID:18042622
  title: Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin.
  findings: []
- id: PMID:20133653
  title: No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro.
  findings: []
- id: PMID:20357208
  title: Cyclin-dependent kinase 5 modulates the transcriptional activity of the mineralocorticoid receptor and regulates expression of brain-derived neurotrophic factor.
  findings: []
- id: PMID:20559324
  title: Cables1 protects p63 from proteasomal degradation to ensure deletion of cells after genotoxic stress.
  findings: []
- id: PMID:21145489
  title: The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose.
  findings: []
- id: PMID:21220307
  title: Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control.
  findings: []
- id: PMID:21473899
  title: 'Cdk5: multitasking between physiological and pathological conditions.'
  findings:
  - statement: Review summarizing CDK5 as a proline-directed serine/threonine kinase linked to neuronal migration, cortical layering, synaptic plasticity, and neurodegenerative dysregulation.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review article supporting high-level CDK5 neuronal and 
      neurodegeneration framing; useful synthesis but not primary experimental
      evidence.
- id: PMID:21499257
  title: Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease.
  findings:
  - statement: CDK5 phosphorylates SH3GLB1/endophilin B1 and is required for induced neuronal autophagy in starvation and Parkinson disease models.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract directly supports CDK5-mediated 
      phosphorylation of endophilin B1/SH3GLB1 and CDK5 requirement for induced
      neuronal autophagy.
- id: PMID:22078880
  title: "Adipocyte NCoR knockout decreases PPAR\u03B3 phosphorylation and enhances PPAR\u03B3 activity and insulin sensitivity."
  findings: []
- id: PMID:22745285
  title: Synaptic vesicle pools and dynamics.
  findings: []
- id: PMID:23455922
  title: Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS.
  findings: []
- id: PMID:23543736
  title: Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel potentiator of cyclin-dependent kinases to enhance cell proliferation independently of its hydrolase activity.
  findings: []
- id: PMID:23602568
  title: The protein interaction landscape of the human CMGC kinase group.
  findings: []
- id: PMID:24548080
  title: CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration.
  findings: []
- id: PMID:24607229
  title: Memory enhancement by targeting Cdk5 regulation of NR2B.
  findings:
  - statement: CDK5 phosphorylates NR2B/GluN2B Ser1116, regulating NMDAR surface expression, synaptic transmission, and memory.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full-text record supports CDK5 phosphorylation of 
      NR2B/GluN2B and regulation of NMDA receptor surface expression, synaptic
      transmission, and memory.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  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:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
- id: PMID:27107012
  title: Pooled-matrix protein interaction screens using Barcode Fusion Genetics.
  findings: []
- id: PMID:28386764
  title: Roles of tau protein in health and disease.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:30833792
  title: A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
  findings: []
- id: PMID:32812023
  title: Phosphorylated tau interactome in the human Alzheimer's disease brain.
  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: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:35016035
  title: Identification and functional characterization of transcriptional activators in human cells.
  findings: []
- id: PMID:35063084
  title: Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:7834371
  title: Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems.
  findings: []
- id: PMID:8090221
  title: p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports CDK5 activation by the neuronal p35 
      regulatory subunit and the CDK5-p35 kinase-complex model.
- id: Reactome:R-HSA-180047
  title: CDK5 phosphorylates DARPP-32 on Thr75
  findings: []
- id: Reactome:R-HSA-399944
  title: Phosphorylation of CRMPs by Cdk5
  findings: []
- id: Reactome:R-HSA-399951
  title: Phosphorylation of CRMPs by GSK3beta
  findings: []
- id: Reactome:R-HSA-6805276
  title: CDK5 phosphorylates TP53
  findings: []
- id: Reactome:R-HSA-8863007
  title: p25-bound CDK5 phosphorylates CDC25B
  findings: []
- id: Reactome:R-HSA-8863011
  title: p25-bound CDK5 phosphorylates CDC25C
  findings: []
- id: Reactome:R-HSA-8863013
  title: CDK5 binds p25
  findings: []
- id: Reactome:R-HSA-8863014
  title: p25-bound CDK5 phosphorylates CDC25A
  findings: []
- id: Reactome:R-HSA-8863587
  title: CDK5:p25 translocates to the nucleus
  findings: []
- id: Reactome:R-NUL-9032945
  title: Ntrk2 phosohorylates CDK5
  findings: []
- id: file:human/CDK5/CDK5-uniprot.txt
  title: UniProtKB record for human CDK5
  findings:
  - statement: UniProt summarizes CDK5 as a proline-directed serine/threonine kinase activated by CDK5R1/CDK5R2, with neuronal, synaptic, cytoskeletal, apoptosis, and substrate-specific autophagy functions.
- id: file:human/CDK5/CDK5-notes.md
  title: CDK5 review notes
  findings:
  - statement: Manual PN-focused CDK5 notes; Drosophila Cdk5-Acinus autophagy evidence was treated as context only, while human SH3GLB1/endophilin B1 evidence supported regulation of macroautophagy.
core_functions:
- molecular_function:
    id: GO:0004693
    label: cyclin-dependent protein serine/threonine kinase activity
  description: CDK5 is a CDK5R-activated proline-directed serine/threonine kinase that phosphorylates neuronal, synaptic, cytoskeletal, stress-response, and autophagy-associated substrates.
  directly_involved_in:
  - id: GO:0007409
    label: axonogenesis
  - id: GO:0001764
    label: neuron migration
  - id: GO:0030182
    label: neuron differentiation
  - id: GO:0031175
    label: neuron projection development
  - id: GO:0048675
    label: axon extension
  - id: GO:0007416
    label: synapse assembly
  - id: GO:0016079
    label: synaptic vesicle exocytosis
  - id: GO:0048488
    label: synaptic vesicle endocytosis
  - id: GO:0048167
    label: regulation of synaptic plasticity
  - id: GO:0051966
    label: regulation of synaptic transmission, glutamatergic
  - id: GO:0061001
    label: regulation of dendritic spine morphogenesis
  - id: GO:0016241
    label: regulation of macroautophagy
  locations:
  - id: GO:0014069
    label: postsynaptic density
  - id: GO:0030426
    label: growth cone
  - id: GO:0045202
    label: synapse
  - id: GO:0030424
    label: axon
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  in_complex:
    id: GO:0016533
    label: protein kinase 5 complex
  supported_by:
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Proline-directed serine/threonine-protein kinase
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39)
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
  - reference_id: PMID:21473899
    supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity
  - reference_id: PMID:24607229
    supporting_text: controls the receptor's cell surface expression
  - reference_id: PMID:21499257
    supporting_text: unexpected role for Cdk5 in the regulation of induced autophagy in neurons
  - reference_id: PMID:21499257
    supporting_text: autophagy induction in starved neurons
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons
- molecular_function:
    id: GO:0004693
    label: cyclin-dependent protein serine/threonine kinase activity
  description: In proliferating (non-neuronal) cells CDK5 partners with cyclin B1, rather than its neuronal p35/p39 activators, and is active during mitosis; this CDK5-cyclin B1 complex behaves as a canonical CDK-cyclin kinase that phosphorylates mitotic substrates to safeguard mitotic fidelity and genome stability.
  directly_involved_in:
  - id: GO:0051726
    label: regulation of cell cycle
  - id: GO:1901987
    label: regulation of cell cycle phase transition
  supported_by:
  - reference_id: PMID:39232161
    supporting_text: CDK5 is active throughout mitosis
  - reference_id: PMID:39232161
    supporting_text: cyclin B1 is a mitotic co-factor of CDK5
  - reference_id: file:human/CDK5/CDK5-deep-research-falcon.md
    supporting_text: CDK5 can form a complex with cyclin B1 and regulate mitotic fidelity, challenging the traditional view that CDK5 has no cell cycle function
- molecular_function:
    id: GO:0050321
    label: tau-protein kinase activity
  description: CDK5 phosphorylates MAPT/tau and other microtubule-associated neuronal substrates, contributing to cytoskeletal regulation and neurodegeneration-relevant tau biology.
  directly_involved_in:
  - id: GO:0000226
    label: microtubule cytoskeleton organization
  locations:
  - id: GO:0043005
    label: neuron projection
  - id: GO:0043025
    label: neuronal cell body
  supported_by:
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: MAPT/TAU, MAP2, MAP1B
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B)
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Proline-directed serine/threonine-protein kinase
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein]
  - reference_id: file:human/CDK5/CDK5-uniprot.txt
    supporting_text: Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission
  - reference_id: PMID:21473899
    supporting_text: normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity
proposed_new_terms: []
suggested_questions:
- question: Should human CDK5 be curated directly to basal autophagy/autophagosome maturation based on conserved Acinus regulation, or only to SH3GLB1-dependent regulation of induced macroautophagy?
  experts:
  - GO autophagy editors
  - CDK5 neuronal signaling experts
  - Drosophila autophagy experts
- question: Which CDK5 substrate-binding annotations should be retained as specific MF annotations versus represented as phosphorylation/regulatory process annotations?
  experts:
  - GO molecular-function editors
  - neurobiology curators
suggested_experiments:
- description: Test whether human CDK5 phosphorylates ACIN1 at sites corresponding to Drosophila Acinus S437 and whether this affects basal autophagy flux or autophagosome maturation in neuronal cells.
  hypothesis: The Drosophila Cdk5-Acinus basal-autophagy module is conserved only if human CDK5 directly phosphorylates ACIN1 and changes basal autophagic flux.
  experiment_type: kinase assay/autophagy flux assay
- description: Dissect CDK5-dependent SH3GLB1/endophilin B1 phosphorylation from other CDK5 neuronal substrates using phosphosite-specific rescue mutants in starved neurons.
  hypothesis: CDK5 regulation of macroautophagy is mediated through SH3GLB1 phosphorylation rather than a general CDK5 role in all autophagy steps.
  experiment_type: phosphosite rescue/autophagy imaging
- description: Using the analog-sensitive CDK5 chemical-genetic system from Zheng et al. 2024, map the mitotic CDK5-cyclin B1 phosphoproteome in non-neuronal proliferating cells and compare it to the CDK1-cyclin B1 substrate set, to determine whether CDK5 cell-cycle annotations should be refined to specific mitotic substrates/processes.
  hypothesis: CDK5-cyclin B1 phosphorylates a distinct subset of mitotic substrates that ensures chromosome segregation fidelity, separable from CDK1-cyclin B1 activity.
  experiment_type: analog-sensitive kinase phosphoproteomics