WEE1
WEE1 G2 Checkpoint Kinase: A Key Regulator of Cell Cycle Progression and DNA Damage Response
Gene Information Card
| Symbol | WEE1 |
|---|---|
| Full Name | WEE1 G2 checkpoint kinase |
| Gene Type | protein-coding |
| Chromosomal Location | 11p15.4 |
| NCBI Gene ID | 7465 ncbi.nlm.nih.gov/gene/7465 |
| Ensembl ID | ENSG00000166483 |
| UniProt ID | P30291 |
| OMIM ID | 193525 |
| HGNC ID | 12761 |
| Aliases | WEE1A, WEE1hu |
Description
WEE1 is a nuclear kinase that phosphorylates and inactivates cyclin-dependent kinase 1 (CDK1) and CDK2, thereby regulating the G2/M cell cycle checkpoint. It plays a critical role in preventing mitotic entry in response to unreplicated or damaged DNA. WEE1 is a key target in cancer therapy, as its inhibition can force cells with DNA damage into mitosis, leading to mitotic catastrophe.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various solid tumors, leukemia) | WEE1 overexpression or activation promotes G2 checkpoint arrest, allowing DNA repair and resistance to genotoxic therapies. Inhibition of WEE1 abrogates this checkpoint, sensitizing cancer cells to DNA-damaging agents. | PMID: 31604886, PMID: 30737457 |
| Microcephaly (rare) | Biallelic loss-of-function mutations in WEE1 have been associated with primary microcephaly, likely due to impaired cell cycle progression in neural progenitors. | PMID: 28575650 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 12.5 | High |
| Bone marrow | 8.2 | Medium |
| Lymph node | 6.7 | Medium |
| Brain | 4.1 | Low |
| Liver | 2.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical carcinoma) | 15.8 | High expression; used in WEE1 functional studies |
| MCF7 (breast carcinoma) | 10.2 | Moderate expression; sensitive to WEE1 inhibition |
| A549 (lung carcinoma) | 9.5 | Moderate expression; WEE1i enhances cisplatin sensitivity |
| K562 (leukemia) | 7.1 | Moderate expression; WEE1i induces apoptosis |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1100C>T (p.Ser367Phe) | Missense | <0.1% | Reported in COSMIC; potential loss of kinase activity |
| c.1450G>A (p.Glu484Lys) | Missense | <0.1% | Found in breast cancer; functional impact unknown |
| c.1666C>T (p.Arg556*) | Nonsense | <0.1% | Truncating; likely loss of function; associated with microcephaly |
Mutation functional classification
Loss of Function (LOF)
Nonsense and frameshift mutations (e.g., p.Arg556*) lead to truncated, non-functional protein. Missense mutations in the kinase domain (e.g., p.Ser367Phe) may reduce catalytic activity.
Gain of Function (GOF)
Not well documented; WEE1 overexpression in tumors is often due to transcriptional upregulation rather than activating mutations.
Dominant Negative (DN)
No confirmed dominant-negative mutations reported in WEE1.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Cell Cycle
• Mitotic (Reactome: R-HSA-69278)
• G2/M DNA damage checkpoint (Reactome: R-HSA-69481)
• p53-independent G1/S DNA damage checkpoint (Reactome: R-HSA-69656)
• Cyclin A/B1 associated events during G2/M transition (Reactome: R-HSA-69202)
Protein Summary
WEE1 is a 646-amino acid serine/threonine protein kinase (UniProt P30291) with an N-terminal regulatory domain and a C-terminal catalytic domain. It phosphorylates CDK1 on Tyr15 and CDK2 on Tyr15, inhibiting their activity. WEE1 is essential for the G2/M checkpoint and is degraded by the proteasome upon mitotic entry. Its expression is cell cycle-regulated, peaking in S and G2 phases. WEE1 is a validated drug target; inhibitors such as adavosertib (AZD1775) are in clinical trials.
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