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UniProtKB/Swiss-Prot P42771 (CD2A1_HUMAN)
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November 4, 2008.
Version 101.
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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents
Names and origin
| Protein names | Recommended name: Cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3 Alternative name(s): Cyclin-dependent kinase 4 inhibitor A Short name=CDK4I p16-INK4a Short name=p16INK4A Short name=p16-INK4 Multiple tumor suppressor 1 Short name=MTS-1 | ||||
| Gene names |
| ||||
| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 156 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein. |
| Subunit structure | Heterodimer with CDK4 or CDK6. Isoform 3 does not bind to CDK4. |
| Tissue specificity | Widely expressed but not detected in brain or skeletal muscle. Isoform 3 is pancreas-specific. |
| Polymorphism | Genetic variations in CDKN2A may underlie susceptibility to uveal melanoma [MIM:155720]. Uveal melanoma is the most common type of ocular malignant tumor, consisting of overgrowth of uveal melanocytes and often preceded by a uveal nevus. |
| Involvement in disease | Defects in CDKN2A are involved in tumor formation in a wide range of tissues. Defects in CDKN2A are the cause of cutaneous malignant melanoma 2 (CMM2) [MIM:155601]. Inheritance is autosomal dominant. Malignant melanoma is a malignant neoplasm of melanocytes, arising de novo or from a preexisting benign nevus, which occurs most often in the skin but also may involve other sites. Defects in CDKN2A are the cause of familial atypical multiple mole melanoma-pancreatic carcinoma syndrome (FAMMMPC) [MIM:606719]. Defects in CDKN2A are a cause of Li-Fraumeni syndrome (LFS) [MIM:151623]. LFS is a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Defects in CDKN2A are the cause of melanoma-astrocytoma syndrome [MIM:155755]. The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma. |
| Sequence similarities | Belongs to the CDKN2 cyclin-dependent kinase inhibitor family. Contains 4 ANK repeats. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| AURKA | O14965 | 1 | EBI-375053,EBI-448680 | |
| CDC45L | O75419 | 1 | EBI-375053,EBI-374969 | |
| CDC6 | Q99741 | 1 | EBI-375053,EBI-374862 | |
| CDC7 | O00311 | 1 | EBI-375053,EBI-374980 | |
| CDK4 | P11802 | 5 | EBI-375053,EBI-295644 | |
| CDK6 | Q00534 | 5 | EBI-375053,EBI-295663 | |
| GMNN | O75496 | 1 | EBI-375053,EBI-371669 | |
| MCM10 | Q7L590 | 1 | EBI-375053,EBI-374912 | |
| MCM2 | P49736 | 1 | EBI-375053,EBI-374819 | |
| MCM5 | P33992 | 1 | EBI-375053,EBI-359410 | |
| MCM6 | Q14566 | 1 | EBI-375053,EBI-374900 | |
| ORC4L | O43929 | 1 | EBI-375053,EBI-374889 | |
| ORC5L | O43913 | 1 | EBI-375053,EBI-374928 | |
| PCNA | P12004 | 3 | EBI-375053,EBI-358311 |
Alternative products
| This entry describes 4 isoforms produced by alternative splicing. [Align] [Select] Notes: Isoform 1 and isoform 4 arise due to the use of two alternative first exons joined to a common exon 2 at the same acceptor site but in different reading frames, resulting in two completely different isoforms. | ||||||
| Isoform 1 (identifier: P42771-1) Also known as: p16INK4a; This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. | ||||||
| Isoform 2 (identifier: P42771-2) The sequence of this isoform differs from the canonical sequence as follows: 1-51: Missing. | ||||||
| Isoform 3 (identifier: P42771-3) Also known as: p12; The sequence of this isoform differs from the canonical sequence as follows: 52-116: MMMGSARVAE...RDAWGRLPVD → GRRSAAGAGD...LGAWETKEEE 117-156: Missing. | ||||||
| Isoform 4 (identifier: Q8N726-1) Also known as: p14ARF; p19ARF; ARF; The sequence of this isoform can be found in the external entry Q8N726-1. Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 156 | 156 | Cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3 | PRO_0000144177 | |||||
Regions | |||||||||
| Repeat | 11 – 40 | 30 | ANK 1 | ||||||
| Repeat | 44 – 72 | 29 | ANK 2 | ||||||
| Repeat | 77 – 106 | 30 | ANK 3 | ||||||
| Repeat | 110 – 139 | 30 | ANK 4 | ||||||
Natural variations | |||||||||
| Alternative sequence | 1 – 51 | 51 | Missing in isoform 2. | VSP_015864 | |||||
| Alternative sequence | 52 – 116 | 65 | MMMGS…RLPVD → GRRSAAGAGDGGRLWRTKFA GELESGSASILRKKGRLPGE FSEGVCNHRPPPGDALGAWE TKEEE in isoform 3. | VSP_015865 | |||||
| Alternative sequence | 117 – 156 | 40 | Missing in isoform 3. | VSP_015866 | |||||
| Natural variant | 14 | 1 | D → E in a biliary tract tumor. | VAR_001408 | |||||
| Natural variant | 16 | 1 | L → P in a biliary tract tumor and a familial melanoma. | VAR_001409 | |||||
| Natural variant | 20 | 1 | A → P in a lung tumor and melanoma. | VAR_001410 | |||||
| Natural variant | 20 | 1 | A → S in a biliary tract tumor. | VAR_001411 | |||||
| Natural variant | 23 | 1 | G → D in a pancreas tumor. | VAR_001412 | |||||
| Natural variant | 24 | 1 | R → C in melanoma. | VAR_001413 | |||||
| Natural variant | 24 | 1 | R → P in CMM2 and melanoma. | VAR_001414 | |||||
| Natural variant | 26 | 1 | E → D in a biliary tract tumor. | VAR_001415 | |||||
| Natural variant | 32 | 1 | L → P in CMM2. | VAR_001416 | |||||
| Natural variant | 33 | 1 | E → D in a biliary tract tumor. | VAR_001417 | |||||
| Natural variant | 35 | 1 | G → A in CMM2 and a biliary tract tumor. | VAR_001418 | |||||
| Natural variant | 35 | 1 | G → E in melanoma. | VAR_001419 | |||||
| Natural variant | 48 | 1 | P → L in melanoma and a head and neck tumor; somatic mutation. | VAR_001420 | |||||
| Natural variant | 49 | 1 | I → S in a biliary tract tumor. | VAR_001421 | |||||
| Natural variant | 49 | 1 | I → T | VAR_001422 | |||||
| Natural variant | 50 | 1 | Q → R in CMM2. | VAR_001423 | |||||
| Natural variant | 53 | 1 | M → I in CMM2. | VAR_001424 | |||||
| Natural variant | 56 | 1 | S → I Possible polymorphism. | VAR_001425 | |||||
| Natural variant | 57 | 1 | A → V in pancreas carcinoma; somatic mutation. | VAR_001426 | |||||
| Natural variant | 59 | 1 | V → G in CMM2. | VAR_001427 | |||||
| Natural variant | 60 | 1 | A → T | VAR_001428 | |||||
| Natural variant | 61 – 62 | 2 | EL → DV | VAR_001429 | |||||
| Natural variant | 62 | 1 | L → P in familial melanoma. | VAR_001430 | |||||
| Natural variant | 66 | 1 | H → Y in non-small cell lung carcinoma. | VAR_001431 | |||||
| Natural variant | 68 | 1 | A → L in familial melanoma; requires 2 nucleotide substitutions. | VAR_001432 | |||||
| Natural variant | 68 | 1 | A → T in an esophagus tumor. | VAR_001433 | |||||
| Natural variant | 68 | 1 | A → V | VAR_001434 | |||||
| Natural variant | 69 | 1 | E → K in a bladder tumor. | VAR_001435 | |||||
| Natural variant | 69 | 1 | E → V in a lung tumor. | VAR_001436 | |||||
| Natural variant | 71 | 1 | N → K in familial melanoma. | VAR_001437 | |||||
| Natural variant | 71 | 1 | N → S | VAR_001438 | |||||
| Natural variant | 72 | 1 | C → G in an esophagus tumor. | VAR_001439 | |||||
| Natural variant | 74 | 1 | D → N in a bladder tumor. | VAR_001440 | |||||
| Natural variant | 74 | 1 | D → V in a biliary tract tumor. | VAR_001441 | |||||
| Natural variant | 80 | 1 | R → L in a head and neck tumor. | VAR_001442 | |||||
| Natural variant | 81 | 1 | P → L in melanoma; impairs the function. dbSNP rs11552823. | VAR_001443 | |||||
| Natural variant | 83 | 1 | H → N in a lung tumor. | VAR_001445 | |||||
| Natural variant | 83 | 1 | H → Y in a pancreas and a head and neck tumor. | VAR_001444 | |||||
| Natural variant | 84 | 1 | D → E in a bladder tumor. | VAR_001446 | |||||
| Natural variant | 84 | 1 | D → H in non-small cell lung carcinoma. | VAR_001447 | |||||
| Natural variant | 84 | 1 | D → N in an esophagus, a head and neck and a lung tumor. | VAR_001448 | |||||
| Natural variant | 84 | 1 | D → Y in CMM2; also found in a lung and a prostate tumor. dbSNP rs11552822. | VAR_001449 | |||||
| Natural variant | 85 | 1 | A → T | VAR_001450 | |||||
| Natural variant | 87 | 1 | R → P in CMM2; impairs the function. | VAR_001451 | |||||
| Natural variant | 87 | 1 | R → W in CMM2. | VAR_012317 | |||||
| Natural variant | 88 | 1 | E → D in a biliary tract tumor. | VAR_001452 | |||||
| Natural variant | 89 | 1 | G → D in melanoma; somatic mutation. | VAR_001453 | |||||
| Natural variant | 89 | 1 | G → S in melanoma. | VAR_001454 | |||||
| Natural variant | 93 | 1 | T → A in non-small cell lung carcinoma. | VAR_001455 | |||||
| Natural variant | 94 | 1 | L → Q in melanoma. | VAR_023604 | |||||
| Natural variant | 95 | 1 | V → A in non-small cell lung carcinoma. | VAR_001456 | |||||
| Natural variant | 97 | 1 | L → R Possible polymorphism. | VAR_001457 | |||||
| Natural variant | 98 | 1 | H → P in melanoma. | VAR_001458 | |||||
| Natural variant | 98 | 1 | H → Q in melanoma. | VAR_001459 | |||||
| Natural variant | 99 | 1 | R → P in familial melanoma. | VAR_001460 | |||||
| Natural variant | 99 | 1 | R → Q in non-small cell lung carcinoma. | VAR_001461 | |||||
| Natural variant | 100 | 1 | A → L in melanoma; requires 2 nucleotide substitutions. | VAR_001462 | |||||
| Natural variant | 100 | 1 | A → P | VAR_001463 | |||||
| Natural variant | 101 | 1 | G → W in CMM2 and FAMMMPC; impairs the function. | VAR_001464 | |||||
| Natural variant | 102 | 1 | A → E in LFS; somatic mutation. | VAR_015818 | |||||
| Natural variant | 104 – 105 | 2 | Missing | VAR_001465 | |||||
| Natural variant | 107 | 1 | R → C in CMM2. | VAR_001466 | |||||
| Natural variant | 107 | 1 | R → H | VAR_001467 | |||||
| Natural variant | 108 | 1 | D → H in a bladder tumor. | VAR_001469 | |||||
| Natural variant | 108 | 1 | D → Y in a head and neck tumor. | VAR_001468 | |||||
| Natural variant | 112 | 1 | R → RR in CMM2. | VAR_035068 | |||||
| Natural variant | 114 | 1 | P → L in non-small cell lung carcinoma. | VAR_001470 | |||||
| Natural variant | 117 | 1 | L → M in melanoma; somatic mutation. | VAR_001471 | |||||
| Natural variant | 118 | 1 | A → T in CMM2. | VAR_001472 | |||||
| Natural variant | 119 | 1 | E → Q in a biliary tract tumor. | VAR_001473 | |||||
| Natural variant | 120 | 1 | E → A in non-small cell lung carcinoma. | VAR_001474 | |||||
| Natural variant | 120 | 1 | E → K in non-small cell lung carcinoma. | VAR_001475 | |||||
| Natural variant | 122 | 1 | G → R in CMM2. | VAR_035069 | |||||
| Natural variant | 122 | 1 | G → S in a biliary tract tumor. | ||||||