CDK4 (human, P11802) — curation notes

Identity and core biology

CDK4 = cyclin-dependent kinase 4 (EC 2.7.11.22), a 303-aa CMGC-group Ser/Thr protein
kinase, CDC2/CDKX subfamily. It is the catalytic subunit of the cyclin D-CDK4 ("DC")
holoenzyme. Its defining, best-established function is to phosphorylate the
retinoblastoma (RB) family pocket proteins RB1/pRb, RBL1/p107 and RBL2/p130 in early-mid
G1, relieving their repression of E2F and driving the G1/S transition.

• UniProt FUNCTION: "Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that
  phosphorylate and inhibit members of the retinoblastoma (RB) protein family including
  RB1 and regulate the cell-cycle during G(1)/S transition." [file:human/CDK4/CDK4-uniprot.txt]
• PMID:19237555
• PMID:22094256
• PMID:19237565

Activation and regulation

• Requires BOTH binding of a D-type cyclin (CCND1/2/3) AND activation-loop phosphorylation
  at Thr172 (UniProt ACTIVITY REGULATION; MOD_RES 172 phosphothreonine).
• Cyclin binding is obligatory and is the meaningful MF underlying the many D-cyclin
  "protein binding" rows. PMID:11896535
• CIP/KIP proteins (p21/CDKN1A, p27/CDKN1B, p57/CDKN1C) both promote assembly and, at
  higher stoichiometry, inhibit; they are assembly factors, not only inhibitors.
  PMID:9106657
• INK4 proteins (p16/CDKN2A, p15/CDKN2B, p18/CDKN2C, p19/CDKN2D) specifically bind and
  inhibit CDK4/6.
  PMID:8259215
  PMID:7603984
• Hsp90-Cdc37 chaperone stabilizes/matures CDK4 before complex assembly.
  PMID:9150368
  PMID:27339980

Localization

Cytoplasmic when uncomplexed; cyclin D-CDK4 assembles in the cytoplasm, accumulates at
the nuclear membrane and enters the nucleus at the G1→S transition, colocalizing with RB1.
Also present in nucleoli and heterochromatin lumps.
PMID:18827403
PMID:18827403
Core functional location = nucleus/nucleoplasm (site of RB phosphorylation); cytosol =
resting/assembly pool.

Metazoan-specific G1 CDK

CDK4/CDK6 with cyclin D are the dedicated metazoan G1 CDKs; the repository module
modules/g1_s_transition.yaml uses CDK4 (UniProtKB:P11802) as the metazoan exemplar of
the "G1 cyclin-dependent kinase" family node (PANTHER:PTHR24056; PAINT node
PTN000623980). GO-CAM gocams/61e0e55600000624 models CDK4 with GO:0004693 acting in
GO:0000082 (G1/S transition).

Curation decisions (summary)

• Molecular function: kinase activity terms (GO:0004693, GO:0106310, GO:0004672,
  GO:0016301), ATP binding (GO:0005524) and cyclin binding (GO:0030332) all ACCEPT — core.
• GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity
  (TAS, Reactome): this MF describes the cyclin/regulatory subunit, not the catalytic
  kinase. CDK4 is the catalyst → MODIFY to GO:0004693.
• Complexes/locations: GO:0000307 (CDK holoenzyme), GO:0097128/9/30 (cyclin
  D1/2/3-CDK4 complexes), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm
  (GO:0005737), cytosol (GO:0005829) ACCEPT. Nuclear membrane (GO:0031965), nucleolus
  (GO:0005730), chromatin (GO:0000785) KEEP_AS_NON_CORE (real but transient/minor pools).
• Over-propagated ortholog IEA CC (GO_REF:0000107): transcription regulator complex
  (GO:0005667) and bicellular tight junction (GO:0005923) → MARK_AS_OVER_ANNOTATED
  (CDK4 phosphorylates transcription factors but is not a structural subunit of these
  complexes; tight-junction localization is a spurious ortholog transfer).
• G1/S (GO:0000082) ACCEPT — core BP. G2/M (GO:0000086, IBA) KEEP_AS_NON_CORE —
  reflects the pan-CDK ancestral node (PTN000623979); CDK4 itself is a G1 kinase.
• GO:0010971 positive regulation of G2/M (IDA, INSM1 paper): the flow-cytometry
  readout of cells reaching G2/M after cyclin D1-CDK4 released a G1/S block; CDK4's direct
  role is at G1/S → MARK_AS_OVER_ANNOTATED.
• Generic/indirect BP: signal transduction (GO:0007165), regulation of gene
  expression (GO:0010468), regulation of cell cycle (GO:0051726), positive regulation of
  cell population proliferation (GO:0008284), positive regulation of fibroblast
  proliferation (GO:0048146) → KEEP_AS_NON_CORE (downstream/general). Regulation of
  transcription initiation by Pol II (GO:0060260, Reactome generic pathway) and response
  to xenobiotic stimulus (GO:0009410, IEP: cdk4 mRNA merely falls after sulindac) →
  MARK_AS_OVER_ANNOTATED.
• GO:0005515 protein binding (167 IPI rows): per repository policy, bare protein
  binding is uninformative. D-cyclin partners (CCND1/P24385, CCND2/P30279, CCND3/P30281)
  → MODIFY to cyclin binding (GO:0030332), the evidence-backed informative MF. All other
  partners (INK4/CIP-KIP inhibitors, HSP90AB1, CDC37, RBL1/2, MYC, CEBPA, APOBEC3B,
  FNIP1/2, FBXW7, RNF26, UCHL1, PSMD10, ZNF655, HOOK1, IKZF3, INCA1, OGDHL, CDK7, and the
  Legionella effector lpg1972) → REMOVE (real interactions, but the bare term carries no
  functional information and no specific MF is invented from interaction data alone). The
  underlying interactions are documented in UniProt SUBUNIT/INTERACTION and remain valid.

Disease

Familial/cutaneous melanoma (CMM3; e.g. R24C variant abrogating p16 binding) and
autosomal-recessive primary microcephaly 31 (MCPH31). CDK4/6 inhibitors (palbociclib,
ribociclib, abemaciclib) are established in HR+/HER2- breast cancer.