MAPK8IP3: JNK-Interacting Protein 3 (JIP3) – Key Scaffold in MAPK Signaling
Comprehensive genomic, functional, and clinical overview of MAPK8IP3, a scaffold protein regulating JNK signaling, implicated in neurodevelopmental disorders and cancer.
Gene Information Card
| Symbol | MAPK8IP3 |
|---|---|
| Full Name | Mitogen-Activated Protein Kinase 8 Interacting Protein 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 16p13.3 |
| NCBI Gene ID | 7157 ncbi.nlm.nih.gov/gene/7157 |
| Ensembl ID | ENSG00000138801 |
| UniProt ID | Q9UQF2 |
| OMIM ID | 605431 |
| HGNC ID | 6882 |
| Aliases | JIP3, JIP-3, FLJ00074, KIAA1066 |
Description
MAPK8IP3 (Mitogen-Activated Protein Kinase 8 Interacting Protein 3) encodes JIP3, a scaffold protein that specifically interacts with MAPK8 (JNK1) and MAPK9 (JNK2) to modulate JNK signaling. JIP3 facilitates the assembly of a functional JNK signaling module by binding to JNK, MKK7, and MLK family members. It is involved in neuronal development, axonal transport, and stress response. Mutations in MAPK8IP3 are associated with neurodevelopmental disorders and have been identified in various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) | Loss-of-function or missense mutations disrupt JIP3-mediated JNK signaling and axonal transport, leading to impaired neuronal development. | ClinVar, OMIM |
| Intellectual disability, autosomal dominant | Heterozygous missense variants in MAPK8IP3 impair JIP3 scaffold function, altering JNK pathway activation. | ClinVar, OMIM |
| Colorectal cancer | Somatic mutations (e.g., missense, frameshift) may alter JIP3 scaffolding, affecting JNK-mediated apoptosis and proliferation. | COSMIC |
| Lung cancer | Recurrent somatic mutations in MAPK8IP3 observed, potentially modulating MAPK signaling in tumorigenesis. | COSMIC |
| Breast cancer | Somatic variants reported, though functional impact remains under investigation. | COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | High |
| Testis | 8.2 | Medium |
| Heart | 6.1 | Medium |
| Liver | 4.3 | Low |
| Kidney | 5.0 | Medium |
| Lung | 3.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.2 | High expression; relevant for neuronal studies |
| HeLa (cervical carcinoma) | 7.8 | Moderate expression |
| HEK293 (embryonic kidney) | 6.5 | Moderate expression |
| A549 (lung carcinoma) | 4.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1645C>T (p.Arg549Trp) | Missense | <0.01% (gnomAD) | Likely pathogenic; associated with neurodevelopmental disorder (ClinVar) |
| c.2023G>A (p.Gly675Arg) | Missense | <0.01% | Pathogenic; disrupts JIP3-JNK interaction (ClinVar) |
| c.1234_1235insA (p.Thr412Asnfs*5) | Frameshift | Rare | Loss-of-function; truncation of scaffold domain (ClinVar) |
| c.788A>G (p.Asn263Ser) | Missense | 0.02% (COSMIC) | Somatic; observed in colorectal cancer (COSMIC) |
| c.1456C>T (p.Pro486Ser) | Missense | 0.01% (COSMIC) | Somatic; lung cancer (COSMIC) |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations (e.g., p.Thr412Asnfs*5) lead to truncated JIP3 lacking the JNK-binding domain, impairing scaffold function and JNK signaling.
Gain of Function (GOF)
Not clearly established; some missense variants may enhance JNK pathway activation, but evidence is limited.
Dominant Negative (DN)
Missense mutations (e.g., p.Arg549Trp) may produce a JIP3 protein that interferes with wild-type scaffold assembly, reducing JNK signaling.
View complete mutation data：
Gene Ontology (GO)
Pathways
• JNK (MAPK) signaling pathway (Reactome: R-HSA-450294)
• MAPK signaling pathway (KEGG: hsa04010)
• Axon guidance (KEGG: hsa04360)
• Neurotrophin signaling pathway (KEGG: hsa04722)
Protein Summary
JIP3 (MAPK8IP3) is a 1336-amino-acid scaffold protein that assembles a JNK signaling module by binding JNK, MKK7, and MLK kinases. It contains an N-terminal JNK-binding domain (JBD) and a C-terminal domain that interacts with kinesin light chain, linking JNK signaling to axonal transport. JIP3 is highly expressed in brain and testis, and its dysfunction is linked to neurodevelopmental disorders and cancer. The protein localizes to the cytoplasm and perinuclear region, and regulates neuronal differentiation, apoptosis, and stress responses.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MAPK8IP3 Knockout HEK293 Cell Line | EDJ-KQ704 | Human | 23162 | Details Get a Quote |
| MAPK8IP3 Knockout A-549 Cell Line | EDJ-KQ18153 | Human | 23162 | Details Get a Quote |
| MAPK8IP3 Knockout HCT 116 Cell Line | EDJ-KQ19293 | Human | 23162 | Details Get a Quote |
| MAPK8IP3 Knockout HeLa Cell Line | EDJ-KQ19294 | Human | 23162 | Details Get a Quote |
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