RAPGEF4 (Rap Guanine Nucleotide Exchange Factor 4)
A key regulator of Rap1 signaling with roles in neuronal function, insulin secretion, and cancer
Gene Information Card
| Symbol | RAPGEF4 |
|---|---|
| Full Name | Rap guanine nucleotide exchange factor 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 2q31.1 |
| NCBI Gene ID | 11069 ncbi.nlm.nih.gov/gene/11069 |
| Ensembl ID | ENSG00000144381 |
| UniProt ID | Q8WZA2 |
| OMIM ID | 606058 |
| HGNC ID | 16629 |
| Aliases | EPAC2, CGEF2, CNR6L, cAMP-GEFII |
Description
RAPGEF4 encodes a member of the Ras-associated guanine nucleotide exchange factor family. The protein, also known as EPAC2, is directly activated by cAMP and functions as a guanine nucleotide exchange factor for the small GTPase Rap1. It plays critical roles in cell adhesion, exocytosis, neuronal development, and insulin secretion. Alternative splicing generates multiple transcript variants.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Intellectual disability | Disrupted cAMP-Rap1 signaling in neurons | ClinVar, OMIM |
| Type 2 diabetes | Impaired insulin secretion from pancreatic beta cells | NCBI Gene, PubMed |
| Colorectal cancer | Altered EPAC2 expression promotes tumor cell migration | COSMIC, PubMed |
| Breast cancer | EPAC2 overexpression correlates with poor prognosis | COSMIC, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | High |
| Pancreas | 8.3 | Medium |
| Adrenal gland | 6.1 | Medium |
| Heart | 4.2 | Low |
| Liver | 1.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.2 | High expression |
| HeLa (cervical carcinoma) | 7.8 | Medium expression |
| MCF7 (breast cancer) | 5.4 | Medium expression |
| HepG2 (hepatocellular carcinoma) | 2.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.226C>T (p.Arg76Trp) | Missense | <0.01% | Reduced cAMP binding affinity |
| c.1003G>A (p.Gly335Ser) | Missense | <0.01% | Impaired Rap1 activation |
| c.1456_1457del (p.Lys486Glufs*12) | Frameshift | <0.01% | Loss of function |
| c.1892A>G (p.Asn631Ser) | Missense | <0.01% | Altered subcellular localization |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations (e.g., p.Lys486Glufs*12) lead to truncated protein lacking GEF activity.
Gain of Function (GOF)
Not well documented; some missense variants may enhance cAMP sensitivity but evidence is limited.
Dominant Negative (DN)
p.Arg76Trp may interfere with wild-type EPAC2 dimerization, reducing overall signaling.
View complete mutation data：
Gene Ontology (GO)
Pathways
• cAMP signaling pathway (Reactome R-HSA-382556)
• Rap1 signaling pathway (KEGG hsa04015)
• Insulin secretion (KEGG hsa04911)
• Axon guidance (KEGG hsa04360)
Protein Summary
The RAPGEF4 protein (EPAC2) contains a Dishevelled/Egl-10/Pleckstrin (DEP) domain, a cyclic nucleotide-binding (CNB) domain, and a Ras exchange motif (REM) domain. Upon cAMP binding, it undergoes a conformational change that activates its GEF activity toward Rap1. EPAC2 is highly expressed in brain and pancreatic beta cells, where it regulates neurotransmitter release and insulin granule exocytosis. Mutations in RAPGEF4 are associated with neurodevelopmental disorders and altered cancer cell behavior.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| RAPGEF4 Knockout HEK293 Cell Line | EDJ-KQ1301 | Human | 11069 | Details Get a Quote |
| RAPGEF4 Knockout HeLa Cell Line | EDJ-KQ20715 | Human | 11069 | Details Get a Quote |
| RAPGEF4 Knockout A-549 Cell Line | EDJ-KQ64057 | Human | 11069 | Details Get a Quote |
| RAPGEF4 Knockout HCT 116 Cell Line | EDJ-KQ72506 | Human | 11069 | Details Get a Quote |
