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Protein

Cyclin-dependent kinase 4

Gene

Cdk4

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. Hypophosphorylates RB1 in early G1 phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex (By similarity).By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Both phosphorylation at Thr-172 and binding of a D-type cyclin are necessary for enzymatic activity. Full activation of the cyclin-D-CDK4 complex appears to require other factors such as recruitment of the substrate via a substrate recruitment motif, and/or formation of the CDKN1B ternary complex. Inhibited by INK4 family members. In resting cells, the non-tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in proliferating cells, tyrosine phosphorylation of CDKN1B allows phosphorylation of Thr-172 of CDK4 and subsequent activation.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei35ATPPROSITE-ProRule annotation1
Active sitei140Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi12 – 20ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • cyclin binding Source: RGD
  • cyclin-dependent protein serine/threonine kinase activity Source: RGD
  • protein-containing complex binding Source: RGD

GO - Biological processi

  • adipose tissue development Source: Ensembl
  • animal organ regeneration Source: RGD
  • cell division Source: UniProtKB-KW
  • cellular response to insulin stimulus Source: Ensembl
  • cellular response to interleukin-4 Source: Ensembl
  • cellular response to ionomycin Source: Ensembl
  • cellular response to lipopolysaccharide Source: Ensembl
  • cellular response to phorbol 13-acetate 12-myristate Source: Ensembl
  • circadian rhythm Source: RGD
  • G1/S transition of mitotic cell cycle Source: GO_Central
  • lens development in camera-type eye Source: RGD
  • negative regulation of cell cycle arrest Source: UniProtKB
  • positive regulation of apoptotic process Source: RGD
  • positive regulation of cell proliferation Source: RGD
  • positive regulation of cell size Source: RGD
  • positive regulation of fibroblast proliferation Source: Ensembl
  • positive regulation of G2/M transition of mitotic cell cycle Source: UniProtKB
  • positive regulation of translation Source: RGD
  • regulation of G2/M transition of mitotic cell cycle Source: GO_Central
  • regulation of insulin receptor signaling pathway Source: Ensembl
  • regulation of lipid biosynthetic process Source: Ensembl
  • regulation of lipid catabolic process Source: Ensembl
  • regulation of multicellular organism growth Source: Ensembl
  • response to hyperoxia Source: RGD
  • response to lead ion Source: RGD
  • response to organic substance Source: RGD
  • response to testosterone Source: RGD
  • response to toxic substance Source: RGD
  • signal transduction Source: GO_Central

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processCell cycle, Cell division
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.22 5301
ReactomeiR-RNO-187577 SCF(Skp2)-mediated degradation of p27/p21
R-RNO-2559580 Oxidative Stress Induced Senescence
R-RNO-2559582 Senescence-Associated Secretory Phenotype (SASP)
R-RNO-2559585 Oncogene Induced Senescence
R-RNO-3214858 RMTs methylate histone arginines
R-RNO-69229 Ubiquitin-dependent degradation of Cyclin D1
R-RNO-69231 Cyclin D associated events in G1
R-RNO-8849470 PTK6 Regulates Cell Cycle
R-RNO-8878166 Transcriptional regulation by RUNX2

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase 4 (EC:2.7.11.22)
Alternative name(s):
Cell division protein kinase 4
PSK-J3
Gene namesi
Name:Cdk4
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 7

Organism-specific databases

RGDi621120 Cdk4

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000857812 – 303Cyclin-dependent kinase 4Add BLAST302

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineBy similarity1
Modified residuei172Phosphothreonine; by CAKBy similarity1
Modified residuei300PhosphoserineCombined sources1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiP35426
PRIDEiP35426

PTM databases

iPTMnetiP35426
PhosphoSitePlusiP35426

Expressioni

Tissue specificityi

Expressed in fetal and adult lung. Also expressed in brain, heart, liver, skeletal muscle and testes.1 Publication

Developmental stagei

In developing lung, high expression at day 17 after which levels decline to barely detectable levels at birth. Levels then increase postnatally until postnatal day 6 and decline in adulthood. Preferentially expressed in proliferating cells.1 Publication

Gene expression databases

BgeeiENSRNOG00000025602
GenevisibleiP35426 RN

Interactioni

Subunit structurei

Component of the D-CDK4 complex, composed of CDK4 and some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and ZNF655. Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation and enhances the cyclin D-CDK4 complex activity. CDK4 activity is either inhibited or enhanced depending on stoichiometry of complex. The non-tyrosine-phosphorylated form of CDKN1B prevents T-loop phosphorylation of CDK4 producing inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also forms ternary complexes with CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal); the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Interacts with CCND1; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23. Interacts with CEBPA (when phosphorylated). Interacts with FNIP1 and FNIP2.By similarity

GO - Molecular functioni

  • cyclin binding Source: RGD

Protein-protein interaction databases

BioGridi250181, 4 interactors
ComplexPortaliCPX-2075 Cyclin D1-CDK4 complex
CPX-2076 Cyclin D2-CDK4 complex
CPX-2078 Cyclin D3-CDK4 complex
STRINGi10116.ENSRNOP00000034754

Structurei

3D structure databases

ProteinModelPortaliP35426
SMRiP35426
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini6 – 295Protein kinasePROSITE-ProRule annotationAdd BLAST290

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni50 – 56Required for binding D-type cyclinsBy similarity7

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0594 Eukaryota
ENOG410XPP3 LUCA
GeneTreeiENSGT00910000144030
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiP35426
KOiK02089
OMAiATPRYEP
OrthoDBiEOG091G0I1Q
PhylomeDBiP35426

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P35426-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MATTRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGAAGGGLP
60 70 80 90 100
VSTVREVALL RRLEAFEHPN VVRLMDVCAT SRTDRDIKVT LVFEHIDQDL
110 120 130 140 150
RTYLDKAPPP GLPVETIKDL MRQFLSGLDF LHANCIVHRD LKPENILVTS
160 170 180 190 200
NGTVKLADFG LARIYSYQMA LTPVVVTLWY RAPEVLLQST YATPVDMWSV
210 220 230 240 250
GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR EVSLPRGAFS
260 270 280 290 300
PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP LKRISAFRAL QHSYLHKEES

DPE
Length:303
Mass (Da):33,799
Last modified:June 1, 1994 - v1
Checksum:i7E92F2A70B198423
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L11007 mRNA Translation: AAA40903.1
BC070956 mRNA Translation: AAH70956.1
PIRiJN0460
RefSeqiNP_446045.1, NM_053593.2
UniGeneiRn.6115

Genome annotation databases

EnsembliENSRNOT00000031796; ENSRNOP00000034754; ENSRNOG00000025602
GeneIDi94201
KEGGirno:94201

Similar proteinsi

Entry informationi

Entry nameiCDK4_RAT
AccessioniPrimary (citable) accession number: P35426
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: June 20, 2018
This is version 154 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

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