SpermatogenesisOnline 1.0
 

Tag Content
SG ID
SG00000816 
UniProt Accession
Theoretical PI
6.17  
Molecular Weight
33751 Da  
Genbank Nucleotide ID
Genbank Protein ID
Gene Name
Cdk4 
Gene Synonyms/Alias
Crk3 
Protein Name
Cyclin-dependent kinase 4 
Protein Synonyms/Alias
EC=2.7.11.22 CRK3; Cell division protein kinase 4; PSK-J3; 
Organism
Mus musculus (Mouse) 
NCBI Taxonomy ID
10090 
Chromosome Location
chr:10;126500590-126504976;1
View in Ensembl genome browser  
Function in Stage
Function in Cell Type
Description
Cyclin-dependent kinase 4 (Cdk4) and Cdk6, and later Cdk2, in association with their specific cyclin partners, regulate the G1 to S phase cell cycle transition of mammalian cells by phosphorylation of retinoblastoma (Rb) family proteins. Loss of Cdk4 leads to an age-dependent defect in spermatogenesis and disruption in the timing of the estrus cycle.Cdk4 participates in proliferation of beta-islet cells.  
The information of related literatures
1. R. V. Mettus and S. G. Rane (2003) Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. Oncogene 22(52): 8413-21. 

Abstract
Cyclin-dependent kinase 4 (Cdk4) and Cdk6, and later Cdk2, in association with their specific cyclin partners, regulate the G1 to S phase cell cycle transition of mammalian cells by phosphorylation of retinoblastoma (Rb) family proteins. Phosphorylation of Rb results in the release of S-phase specific transcription factors; cell cycle-promoting gene expression, and advancement of the cell cycle. Loss of Cdk4 by homologous-targeted disruption leads to a delay in S-phase entry in serum-stimulated mouse embryo fibroblast (MEF) cultures. Homozygous Cdk4-deficient mice display defects in weight gain, fertility and hypoproliferation of specific endocrine cells of the pituitary and pancreas, the latter of which results in a diabetes-like phenotype. In contrast, inheritance of the p16(Ink4a)-insensitive Cdk4(R24C) mutation leads to spontaneous transformation of MEF cultures in vitro and, in vivo, hyperproliferative disorders that progress to cancer. In this manuscript, we report characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. We observe that, whereas Cdk4 is dispensable for early pancreatic development, normal Cdk4 expression is critical for optimal growth of the organism. Also, we observe that loss of Cdk4 may result in insulin insensitivity, implicating an additional role of Cdk4 in beta-cell function, in addition to its role in beta-cell proliferation. Further, we demonstrate that loss of Cdk4 leads to an age-dependent defect in spermatogenesis and disruption in the timing of the estrus cycle. Taken together, our results indicate that the overall defects in growth, fertility and pancreatic development in Cdk4-deficient mice may be a combination of cell-type specific defects and altered glucose metabolism, as a result of defects in postnatal pancreatic development. PMID: [14627982] 

2. S. G. Rane, P. Dubus, R. V. Mettus, E. J. Galbreath, G. Boden, E. P. Reddy and M. Barbacid (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22(1): 44-52. 

Abstract
To ascertain the role of cyclin-dependent kinase 4 (Cdk4) in vivo, we have targeted the mouse Cdk4 locus by homologous recombination to generate two strains of mice, one that lacks Cdk4 expression and one that expresses a Cdk4 molecule with an activating mutation. Embryonic fibroblasts proliferate normally in the absence of Cdk4 but have a delayed S phase on re-entry into the cell cycle. Moreover, mice devoid of Cdk4 are viable, but small in size and infertile. These mice also develop insulin-deficient diabetes due to a reduction in beta-islet pancreatic cells. In contrast, mice expressing a mutant Cdk4 that cannot bind the cell-cycle inhibitor P16INK4a display pancreatic hyperplasia due to abnormal proliferation of beta-islet cells. These results establish Cdk4 as an essential regulator of specific cell types. PMID: [10319860] 

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Figures for illustrating the function of this protein/gene
Ref: S. G. Rane, P. Dubus, R. V. Mettus, E. J. Galbreath, G. Boden, E. P. Reddy and M. Barbacid (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22(1): 44-52. PMID: [10319860]
Ref: S. G. Rane, P. Dubus, R. V. Mettus, E. J. Galbreath, G. Boden, E. P. Reddy and M. Barbacid (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22(1): 44-52. PMID: [10319860]
Ref: S. G. Rane, P. Dubus, R. V. Mettus, E. J. Galbreath, G. Boden, E. P. Reddy and M. Barbacid (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22(1): 44-52. PMID: [10319860]
Function
Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexesthat phosphorylate and inhibit members of the retinoblastoma (RB)protein family including RB1 and regulate the cell-cycle duringG(1)/S transition. Phosphorylation of RB1 allows dissociation ofthe transcription factor E2F from the RB/E2F complexes and thesubsequent transcription of E2F target genes which are responsiblefor the progression through the G(1) phase. Hypophosphorylates RB1in early G(1) phase. Cyclin D-CDK4 complexes are major integratorsof various mitogenenic and antimitogenic signals. Alsophosphorylates SMAD3 in a cell-cycle-dependent manner andrepresses its transcriptional activity. Component of the ternarycomplex, cyclin D/CDK4/CDKN1B, required for nuclear translocationand activity of the cyclin D-CDK4 complex (By similarity). 
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Subcellular Location
Cytoplasm (By similarity). Nucleus (Bysimilarity). Membrane (By similarity). Note=Cytoplasmic when non-complexed. Forms a cyclin D-CDK4 complex in the cytoplasm as cellsprogress through G(1) phase. The complex accumulates on thenuclear membrane and enters the nucleus on transition from G(1) toS phase. Also present in nucleoli and heterochromatin lumps.Colocalizes with RB1 after release into the nucleus (Bysimilarity). 
Tissue Specificity
 
Gene Ontology
GO IDGO termEvidence
GO:0000785 C:chromatin IEA:Compara.
GO:0000307 C:cyclin-dependent protein kinase holoenzyme complex IPI:MGI.
GO:0005829 C:cytosol IEA:Compara.
GO:0031965 C:nuclear membrane IEA:Compara.
GO:0005730 C:nucleolus IEA:Compara.
GO:0005667 C:transcription factor complex IDA:MGI.
GO:0005524 F:ATP binding IEA:UniProtKB-KW.
GO:0004693 F:cyclin-dependent protein kinase activity IDA:MGI.
GO:0051301 P:cell division IEA:UniProtKB-KW.
GO:0000082 P:G1/S transition of mitotic cell cycle IEA:Compara.
GO:0048146 P:positive regulation of fibroblast proliferation IEA:Compara.
GO:0051726 P:regulation of cell cycle IDA:MGI.
GO:0042127 P:regulation of cell proliferation IMP:MGI.
GO:0010468 P:regulation of gene expression IEA:Compara.
GO:0042493 P:response to drug IEA:Compara.
GO:0007165 P:signal transduction IDA:MGI.
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Interpro
IPR011009;    Kinase-like_dom.
IPR000719;    Prot_kinase_cat_dom.
IPR017441;    Protein_kinase_ATP_BS.
IPR002290;    Ser/Thr_dual-sp_kinase_dom.
IPR008271;    Ser/Thr_kinase_AS.
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Pfam
PF00069;    Pkinase;    1.
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SMART
SM00220;    S_TKc;    1.
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PROSITE
PS00107;    PROTEIN_KINASE_ATP;    1.
PS50011;    PROTEIN_KINASE_DOM;    1.
PS00108;    PROTEIN_KINASE_ST;    1.
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PRINTS
Created Date
18-Oct-2012 
Record Type
Experiment identified 
Protein sequence Annotation
INIT_MET      1      1       Removed (By similarity).
CHAIN         2    303       Cyclin-dependent kinase 4.
                             /FTId=PRO_0000085779.
DOMAIN        6    295       Protein kinase.
NP_BIND      12     20       ATP (By similarity).
REGION       50     56       Required for binding D-type cyclins (By
                             similarity).
ACT_SITE    140    140       Proton acceptor (By similarity).
BINDING      35     35       ATP (By similarity).
MOD_RES       2      2       N-acetylalanine (By similarity).
MOD_RES     150    150       Phosphoserine (By similarity).
MOD_RES     172    172       Phosphothreonine; by CAK.
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Nucleotide Sequence
Length: 912 bp   Go to nucleotide: FASTA
Protein Sequence
Length: 303 bp   Go to amino acid: FASTA
The verified Protein-Protein interaction information
Other Protein-Protein interaction resources
String database  
View Microarray data
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