Nomenclature
Short Name:
CDK6
Full Name:
Cyclin-dependent kinase 6
Alias:
- CRK2
- Cyclin-dependent kinase 6
- EC 2.7.11.22
- Kinase Cdk6
- PLSTIRE
- Serine/threonine protein kinase PLSTIRE
Classification
Type:
Protein-serine/threonine kinase
Group:
CMGC
Family:
CDK
SubFamily:
CDK4
Specific Links
Structure
Mol. Mass (Da):
36,938
# Amino Acids:
326
# mRNA Isoforms:
1
mRNA Isoforms:
36,938 Da (326 AA; Q00534)
4D Structure:
NA
3D Structure:
1D Structure:
3D Image (rendered using PV Viewer):
PDB ID
Subfamily Alignment
Domain Distribution:
| Start | End | Domain |
|---|---|---|
| 13 | 300 | Pkinase |
Kinexus Products
Click on entries below for direct links to relevant products from Kinexus for this protein kinase.
hiddentext
Post-translation Modifications
For detailed information on phosphorylation of this kinase go to PhosphoNET
Acetylated:
K3, K43 (N6), K264 (N6).
Serine phosphorylated:
S57, S86, S155, S222, S223, S290, S293, S296, S317, S321.
Threonine phosphorylated:
T49, T70, T177+, T325.
Tyrosine phosphorylated:
Y13-, Y24-, Y292, Y299.
Ubiquitinated:
K26, K29, K147, K230, K257, K264, K274, K279, K287, K307.
Distribution
Based on gene microarray analysis from the NCBI
Human Tissue Distribution
% Max Expression:
Mean Expression:
Number of Samples:
Standard Deviation:
% Max Expression:
Mean Expression:
Number of Samples:
Standard Deviation:
37
1479
68
1389
1.3
51
28
61
1.3
53
8
56
11
455
262
1498
15
599
81
497
2
70
142
160
5
207
102
460
100
4048
69
7673
5
187
20
172
3
102
257
117
2
71
47
79
13
510
253
550
0.5
21
30
31
1
40
21
33
2
77
42
97
1.1
45
47
44
4
179
463
1670
1.1
45
23
59
1.1
43
206
42
17
674
280
633
1.1
44
40
44
1.5
60
44
76
2
86
18
84
2
87
24
141
4
159
40
330
57
2293
168
5524
0.6
26
36
56
1.1
46
24
39
0.7
30
24
31
2
75
112
73
22
873
24
874
24
982
66
3184
16
664
178
1221
16
667
213
593
2
91
113
106
Evolution
Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
100
100
100
0
0
100
65.6
76
100
-
-
97.5
-
-
-
96.6
97.5
97
-
-
-
96.3
98.1
96
65
76
97
-
-
-
56.1
58.5
-
43.5
61.9
91
65.3
77.9
87
76
83.1
87
-
-
-
42.6
63.7
47
37.6
50.5
-
-
-
41
50.6
63
-
-
-
-
44.4
62.2
-
-
-
-
44.7
62.2
-
40.1
59.8
-
-
-
-
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
Binding Proteins
Examples of known interacting proteins
hiddentext
| No. | Name – UniProt ID |
|---|---|
| 1 | CDKN2A - P42771 |
| 2 | MCM10 - Q7L590 |
| 3 | CDKN2A - Q8N726 |
| 4 | SUMO1 - P63165 |
| 5 | CCND3 - P30281 |
| 6 | CCND1 - P24385 |
| 7 | MCM2 - P49736 |
| 8 | CDKN2C - P42773 |
| 9 | CDKN2D - P55273 |
| 10 | CDKN2B - P42772 |
| 11 | RB1 - P06400 |
| 12 | CDC37 - Q16543 |
| 13 | CCND2 - P30279 |
| 14 | CDKN1B - P46527 |
| 15 | RUNX1 - Q01196 |
Regulation
Activation:
Phosphorylation at Thr-177 increases phosphotransferase activity.
Inhibition:
NA
Synthesis:
NA
Degradation:
Down-regulated in response to enterovirus 71 (EV71) infection.
Known Upstream Kinases
For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET
predictions.
Based on in vitro and/or in vivo phosphorylation data
| Kinase Short Name | UniProt ID (Human) | Phosphosite Location | Phosphosite Sequence | Effect of Phosphorylation |
|---|
Known Downstream Substrates
For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET
predictions.
Based on in vitro and/or in vivo phosphorylation data
| Substrate Short Name | UniProt ID (Human) | Phosphosite Location | Phosphosite Sequence | Effect of Phosphorylation |
|---|
| AML1 (RUNX1) | Q01196 | S249 | DTRQIQPSPPWSYDQ | + |
| AML1 (RUNX1) | Q01196 | S266 | QYLGSIASPSVHPAT | |
| AML1 (RUNX1) | Q01196 | S276 | VHPATPISPGRASGM | |
| AML1 (RUNX1) | Q01196 | T273 | SPSVHPATPISPGRA | + |
| Bcl-2 | P10415 | S70 | RDPVARTSPLQTPAA | |
| Bcl-2 | P10415 | S87 | AAAGPALSPVPPVVH | + |
| Caldesmon | Q05682 | S759 | KTPDGNKSPAPKPSD | |
| Caldesmon | Q05682 | S789 | QSVDKVTSPTKV___ | |
| Caldesmon | Q05682 | T730 | SSPTAAGTPNKETAG | |
| Caldesmon | Q05682 | T753 | INEWLTKTPDGNKSP | |
| Cip1 (p21, CDKN1A) | P38936 | S129 | SGEQAEGSPGGPGDS | - |
| CUGBP1 | Q92879 | S302 | TSSGSSPSSSSSNSV | + |
| FOXM1 | Q08050 | T611 | ETLPISSTPSKSVLP | + |
| p27Kip1 | P46527 | S10 | NVRVSNGSPSLERMD | - |
| p27Kip1 | P46527 | T187 | NAGSVEQTPKKPGLR | + |
| Rb | P06400 | S249 | AVIPINGSPRTPRRG | |
| Rb | P06400 | S612 | MYLSPVRSPKKKGST | - |
| Rb | P06400 | S780 | STRPPTLSPIPHIPR | - |
| Rb | P06400 | S788 | PIPHIPRSPYKFPSS | - |
| Rb | P06400 | S795 | SPYKFPSSPLRIPGG | - |
| Rb | P06400 | S807 | PGGNIYISPLKSPYK | - |
| Rb | P06400 | S811 | IYISPLKSPYKISEG | - |
| Rb | P06400 | T252 | PINGSPRTPRRGQNR | |
| Rb | P06400 | T821 | KISEGLPTPTKMTPR | - |
| Rb | P06400 | T826 | LPTPTKMTPRSRILV | - |
| Rb-like 2 | Q08999 | S1035 | NMDAPPLSPYPFVRT | - |
| Rb-like 2 | Q08999 | S672 | TLYDRYSSPPASTTR | - |
| Rb-like 2 | Q08999 | T401 | SKALRISTPLTGVRY | - |
Protein Kinase Specificity
Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites
Matrix Type:
Experimentally derived from alignment of 30 known protein substrate phosphosites.
Domain #:
1
Inhibitors
For further details on these inhibitors click on the Compound Name and enter it into DrugKiNET or click on the ID's
Based on in vitro and/or in vivo phosphorylation data
| Compound Name | KD, Ki or IC50 (nM) | PubChem ID | ChEMBL ID | PubMed ID |
|---|
Disease Linkage
General Disease Association:
Cancer, brain and eye disorders
Specific Diseases (Non-cancerous):
Primary autosomal recessive microcephaly Type 1; Primary autosomal recessive microcephalies and Seckel syndrome spectrum disorders; Primary autosomal recessive microcephaly Type 12
Specific Cancer Types:
Glioblastoma multiforme (GBM); familial melanomas; gastroesophageal junction adenocarcinomas (AEG)
Comments:
Germline mutations in CDK6 are hypothesized to lead to a predisposition to melanoma. A197T mutation is found in family with autosomal recessive primary microcephaly-12 (MCPH12).
Gene Expression in Cancers:
TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Brain glioblastomas (%CFC= -49, p<0.008); Breast epithelial hyperplastic enlarged lobular units (HELU) (%CFC= -66, p<0.009); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +859, p<0.0001); Malignant pleural mesotheliomas (MPM) tumours (%CFC= -60, p<0.001); and Prostate cancer - primary (%CFC= +62, p<0.0001). The COSMIC website notes an up-regulated expression score for CDK6 in diverse human cancers of 660, which is 1.4-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 7 for this protein kinase in human cancers was 0.1-fold of the average score of 60 for the human protein kinases.
Mutagenesis Experiments:
Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.
Mutation Rate in All Cancers:
Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 25633 diverse cancer specimens. This rate is only -19 % lower than the average rate of 0.075 % calculated for human protein kinases in general.
Mutation Rate in Specific Cancers:
Highest percent mutation rates per 100 amino acids length in human cancers: 0.28 % in 1187 large intestine cancers tested.
Frequency of Mutated Sites:
None > 2 in 20,868 cancer specimens
Comments:
No deletions, insertions or complex mutations are noted on the COSMIC website.