MAPK8IP1

Summary

MAPK8IP1 (mitogen-activated protein kinase 8 interacting protein 1, HGNC:6882) is a protein-coding gene on chromosome 11p11.2, encoding C-Jun-amino-terminal kinase-interacting protein 1 (Q9UQF2). The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module.

This gene encodes a regulator of the pancreatic beta-cell function. It is highly similar to JIP-1, a mouse protein known to be a regulator of c-Jun amino-terminal kinase (Mapk8). This protein has been shown to prevent MAPK8 mediated activation of transcription factors, and to decrease IL-1 beta and MAP kinase kinase 1 (MEKK1) induced apoptosis in pancreatic beta cells. This protein also functions as a DNA-binding transactivator of the glucose transporter GLUT2. RE1-silencing transcription factor (REST) is reported to repress the expression of this gene in insulin-secreting beta cells. This gene is found to be mutated in a type 2 diabetes family, and thus is thought to be a susceptibility gene for type 2 diabetes.

Source: NCBI Gene 9479 — RefSeq curated summary.

At a glance

• Gene–disease (curated): diabetes mellitus, noninsulin-dependent (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 136 total — 1 pathogenic
• Phenotypes (HPO): 5
• MANE Select transcript: NM_005456

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6882
Approved symbol	MAPK8IP1
Name	mitogen-activated protein kinase 8 interacting protein 1
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	IB1, JIP-1, JIP1
Ensembl gene	ENSG00000121653
Ensembl biotype	protein_coding
OMIM	604641
Entrez	9479

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000241014, ENST00000395629, ENST00000497090, ENST00000915944, ENST00000915945

RefSeq mRNA: 1 — MANE Select: NM_005456 NM_005456

CCDS: CCDS7916

Canonical transcript exons

ENST00000241014 — 12 exons

Exon	Start	End
ENSE00000824601	45902372	45903184
ENSE00000824603	45900138	45900452
ENSE00000824604	45898085	45898190
ENSE00001182340	45885651	45885921
ENSE00001522301	45905649	45906465
ENSE00003296149	45901980	45902061
ENSE00003322290	45904718	45904834
ENSE00003358633	45904455	45904564
ENSE00003365785	45904971	45905041
ENSE00003444518	45905151	45905249
ENSE00003444709	45903365	45903440
ENSE00003446000	45903989	45904161

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 98.92.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7506 / max 224.3975, expressed in 392 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114047	2.7654	335
114048	0.8860	227
114054	0.2113	70
114046	0.2076	92
114050	0.1522	69
114053	0.1437	80
114060	0.1107	54
114051	0.0963	51
114045	0.0947	57
114049	0.0551	33

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	98.92	gold quality
right frontal lobe	UBERON:0002810	98.24	gold quality
adenohypophysis	UBERON:0002196	97.74	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.53	gold quality
peripheral nervous system	UBERON:0000010	97.36	gold quality
tibial nerve	UBERON:0001323	97.36	gold quality
anterior cingulate cortex	UBERON:0009835	97.11	gold quality
cerebellar hemisphere	UBERON:0002245	97.05	gold quality
cingulate cortex	UBERON:0003027	97.03	gold quality
cerebellar cortex	UBERON:0002129	96.84	gold quality
cortical plate	UBERON:0005343	96.42	gold quality
prefrontal cortex	UBERON:0000451	96.22	gold quality
ventricular zone	UBERON:0003053	95.38	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.43	gold quality
spinal cord	UBERON:0002240	94.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	94.11	gold quality
amygdala	UBERON:0001876	94.03	gold quality
pituitary gland	UBERON:0000007	93.90	gold quality
middle frontal gyrus	UBERON:0002702	93.86	gold quality
ganglionic eminence	UBERON:0004023	93.82	gold quality
sural nerve	UBERON:0015488	93.69	gold quality
nucleus accumbens	UBERON:0001882	93.61	gold quality
caudate nucleus	UBERON:0001873	93.47	gold quality
cerebellum	UBERON:0002037	93.19	gold quality
paraflocculus	UBERON:0005351	92.70	silver quality
frontal pole	UBERON:0002795	91.95	gold quality
neocortex	UBERON:0001950	91.59	gold quality
putamen	UBERON:0001874	91.52	gold quality
body of pancreas	UBERON:0001150	91.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.48	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR2, REST

miRNA regulators (miRDB)

44 targeting MAPK8IP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-6852-3P	98.54	67.60	1468

Literature-anchored findings (GeneRIF, showing 31)

• Data show that mechanical stress of urothelial cells activates in vivo JNK, as a consequence of a regulated expression of IB1/JIP-1, and that urothelial connexin 26 may be directly regulated by the AP-1 complex. (PMID:12064607)
• role in promoting transcription of amyloid beta protein precursor (PMID:12563035)
• results suggest that JIP-1b may function as a protein linking the kinesin-I motor protein to the cargo receptor, APP, and that the JNK signaling pathway may regulate the phosphorylation of this cargo protein through the JIP-1b scaffold (PMID:12665528)
• Promoter variant is associated with Alzheimer’s disease. (PMID:12740599)
• JIP1 may act as an Akt1 scaffold, which regulates the enzymatic activity of Akt1 and can exert signaling effects independent of JNK activity (PMID:12783873)
• JIP-1 protein may regulate kinesin-I-dependent neuronal AbetaPP transport, which controls AbetaPP processing (PMID:12893827)
• JIP-1 only facilitated (but is not required for) phosphorylation of Amyloid beta protein precursor but not of the two other family members APLP1 (amyloid precursor-like protein 1) and APLP2 (PMID:12917434)
• stability is modulated by intracellular calcium (PMID:14507925)
• Growth control of prostate cancer cells can be mediated through JNK/c-Jun pathway, but androgen responsiveness can be independent of this pathway; androgen independence in progressive prostate cancer may not occur through activation of this pathway. (PMID:15138488)
• High IGF II expression was followed by high expression of JIP-1 in testicular neoplasms. (PMID:15868948)
• IB1/JIP-1 participates to the neuronal phenotype of the human LNCaP cells and is a regulator of JNK signaling pathway (PMID:15894166)
• JIP1 and JIP3, have a cross-talk that leads to the regulation of the ASK1-SEK1-JNK signal during glucose deprivation; cross-talk between JIP3 and JIP1 is mediated through SEK1-JNK2 and Akt1. (PMID:15911620)
• Altogether, our data demonstrate that Akt1 participates in a negative regulatory feedback loop by interacting with the JIP1 scaffold protein. (PMID:15998799)
• the phosphorylation of APP regulates the formation of a pAPP-JIP-1 complex that accumulates in neurites independent of nonphosphorylated APP (PMID:16301330)
• Binding of JIP1 and FEZ1 to Kinesin-1 is sufficient to activate the motor for microtubule binding and motility. (PMID:17200414)
• the activity of JIP1-JNK complexes is downregulated by VRK2 in response to interleukin-1beta (PMID:18286207)
• Thyroid cancers are characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65. (PMID:18480379)
• The pathological Tau/JIP1 interaction requires phosphorylation of Tau, and Tau competes with the physiological binding of JIP1 to kinesin light chain. (PMID:19491104)
• This review discusses the role of the JIP1 and the c-Jun NH(2)-terminal kinase pathway in the molecular pathogenesis of Alzheimer’s and type 2 diabetes. JIP1 is a key regulator of the JNK pathway in neuronal and beta-cells. (PMID:19616077)
• Data suggest that caspase 3-mediated cleavage of JIP1 scaffold proteins may represent an important mechanism for modulation of JNK signalling during apoptotic cell death. (PMID:21237154)
• Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic beta cell death (PMID:23172226)
• In resected pancreatic cancer, carriers of a minor allele for rs3824872 (MAPK8IP1) were associated with a survival advantage compared with noncarriers with an additional 2-year survival if both minor alleles were present. (PMID:23360921)
• Data show that small GTPase RALA regulates formation of a JIP1 (C-Jun-amino-terminal-interacting protein 1) scaffold complex to propagate JNK signaling toward FOXO4 (forkhead box O transcription factor) in response to reactive oxygen species (ROS). (PMID:23770673)
• analysis of the role of JIP1 in APP transport; knockdown of JIP1 did not affect either amyloid precursor protein transport or amyloid-beta peptide production (PMID:23825109)
• All binary complexes (KLC1:APP, KLC1:JIP1, and APP:JIP1) contain conformations with favorable binding free energies indicating that KLC1 and JIP1 may take part in APP transport in Alzheimer’s disease patients. (PMID:27891669)
• extensive biochemical characterization of the KLC:JIP1 interaction, as well as identification of potential KLC1-binding partners, improves the understanding of how this growing family of cargos is recruited to kinesin1 by KLC1. (PMID:30026235)
• Retrospective analysis of the incidence and predictive factors of parametrial involvement in FIGO IB1 cervical cancer. (PMID:33848645)
• Sequential dynein effectors regulate axonal autophagosome motility in a maturation-dependent pathway. (PMID:34014261)
• Identification of Key Biomarkers and Immune Infiltration in Sporadic Vestibular Schwannoma Basing Transcriptome-Wide Profiling. (PMID:35092815)
• Dual Role of Mitogen-Activated Protein Kinase 8 Interacting Protein-1 in Inflammasome and Pancreatic beta-Cell Function. (PMID:36902422)
• Structural basis of homodimerization of the JNK scaffold protein JIP2 and its heterodimerization with JIP1. (PMID:39013462)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	MAPK8IP1	ENSDARG00000090326
danio_rerio	mapk8ip1a	ENSDARG00000102229
mus_musculus	Mapk8ip1	ENSMUSG00000027223
rattus_norvegicus	Mapk8ip1	ENSRNOG00000058478
drosophila_melanogaster	Dab	FBGN0000414
drosophila_melanogaster	numb	FBGN0002973
drosophila_melanogaster	CG8312	FBGN0037720
drosophila_melanogaster	Aplip1	FBGN0040281
drosophila_melanogaster	CG42673	FBGN0261555
caenorhabditis_elegans		WBGENE00000894
caenorhabditis_elegans		WBGENE00001116
caenorhabditis_elegans		WBGENE00002176
caenorhabditis_elegans		WBGENE00003830
caenorhabditis_elegans		WBGENE00009930

Paralogs (11): MAPK8IP2 (ENSG00000008735), NUMBL (ENSG00000105245), NUMB (ENSG00000133961), GULP1 (ENSG00000144366), DAB2 (ENSG00000153071), LDLRAP1 (ENSG00000157978), DAB1 (ENSG00000173406), FAM43B (ENSG00000183114), FAM43A (ENSG00000185112), NOS1AP (ENSG00000198929), C1orf226 (ENSG00000239887)

Protein

Protein identifiers

C-Jun-amino-terminal kinase-interacting protein 1 — Q9UQF2 (reviewed: Q9UQF2)

Alternative names: Islet-brain 1, JNK MAP kinase scaffold protein 1, Mitogen-activated protein kinase 8-interacting protein 1

All UniProt accessions (2): E9PBB9, Q9UQF2

UniProt curated annotations — full annotation on UniProt →

Function. The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins. Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response. Acts as a scaffold protein that coordinates with SH3RF1 in organizing different components of the JNK pathway, including RAC1 or RAC2, MAP3K11/MLK3 or MAP3K7/TAK1, MAP2K7/MKK7, MAPK8/JNK1 and/or MAPK9/JNK2 into a functional multiprotein complex to ensure the effective activation of the JNK signaling pathway. Regulates the activation of MAPK8/JNK1 and differentiation of CD8(+) T-cells.

Subunit / interactions. Forms homo- or heterooligomeric complexes. Binds specific components of the JNK signaling pathway namely, MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAP2K7/MKK7, MAP3K11/MLK3 and DLK1. Also binds the proline-rich domain-containing splice variant of apolipoprotein E receptor 2 (ApoER2). Interacts, via the PID domain, with ARHGEF28. Binds the cytoplasmic tails of LRP1 and LRP2 (Megalin). Binds the TPR motif-containing C-terminal of KNS2, then the pre-assembled MAPK8IP1 scaffolding complexes are transported as a cargo of kinesin, to the required subcellular location. Interacts with the cytoplasmic domain of APP. Interacts with DCLK2. Interacts with MAP3K7/TAK1. Interacts with isoform 1 and isoform 2 of VRK2. Found in a complex with SH3RF1, RAC1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8/JNK1 and MAPK9/JNK2. Interacts with SH3RF2.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus. Endoplasmic reticulum membrane. Mitochondrion membrane.

Tissue specificity. Highly expressed in brain. Expressed in neurons, localizing to neurite tips in differentiating cells. Also expressed in the pancreas, testis and prostate. Low levels in heart, ovary and small intestine. Decreased levels in pancreatic beta cells sensitize cells to IL-1-beta-induced apoptosis.

Post-translational modifications. Phosphorylated by MAPK8, MAPK9 and MAPK10. Phosphorylation on Thr-103 is also necessary for the dissociation and activation of MAP3K12. Phosphorylated by isoform 1 and isoform 2 of VRK2. Hyperphosphorylated during mitosis following activation of stress-activated and MAP kinases. Ubiquitinated. Two preliminary events are required to prime for ubiquitination; phosphorylation and an increased in intracellular calcium concentration. Then, the calcium influx initiates ubiquitination and degradation by the ubiquitin-proteasome pathway.

Disease relevance. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Domain organisation. The destruction boxes (D-box) may act as recognition signals for degradation via the ubiquitin-proteasome pathway. A minimal inhibitory domain prevents pancreatic beta cell apoptosis in vitro, and prevents activation of c-jun by MAPK8, MAPK9 and MAPK10. The SH3 domain mediates homodimerization.

Miscellaneous. A chemically synthesized cell-permeable peptide of the minimal inhibitory domain decreases brain lesions in both transient and permanent ischemia. The level of protection is still high when administered 6 or 12 hours after ischemia.

Similarity. Belongs to the JIP scaffold family.

RefSeq proteins (1): NP_005447* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035638	JIP1_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR047178	JIP1_scaffold	Family

Pfam: PF00640, PF14604

UniProt features (62 total): modified residue 29, compositionally biased region 7, region of interest 7, strand 5, mutagenesis site 4, sequence variant 3, domain 2, short sequence motif 2, chain 1, turn 1, helix 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
7NYO	X-RAY DIFFRACTION	1.4
7NYK	X-RAY DIFFRACTION	1.45
7NYN	X-RAY DIFFRACTION	1.54
7NYM	X-RAY DIFFRACTION	1.61
8RPP	X-RAY DIFFRACTION	1.87
7NYL	X-RAY DIFFRACTION	1.95
7NZB	X-RAY DIFFRACTION	1.96
4H39	X-RAY DIFFRACTION	1.99
4HYU	X-RAY DIFFRACTION	2.15
3OXI	X-RAY DIFFRACTION	2.2
4E73	X-RAY DIFFRACTION	2.27
4IZY	X-RAY DIFFRACTION	2.3
4HYS	X-RAY DIFFRACTION	2.42
3PTG	X-RAY DIFFRACTION	2.43
4G1W	X-RAY DIFFRACTION	2.45
3VUM	X-RAY DIFFRACTION	2.69
3VUH	X-RAY DIFFRACTION	2.7
6FUZ	X-RAY DIFFRACTION	2.7
3VUI	X-RAY DIFFRACTION	2.8
3VUL	X-RAY DIFFRACTION	2.81
3VUK	X-RAY DIFFRACTION	2.95
2H96	X-RAY DIFFRACTION	3
5LW1	X-RAY DIFFRACTION	3.2
3VUG	X-RAY DIFFRACTION	3.24
2G01	X-RAY DIFFRACTION	3.5
2GMX	X-RAY DIFFRACTION	3.5
3VUD	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQF2-F1	55.03	0.18

Antibody-complex structures (SAbDab): 1 — 6FUZ

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (29): 15, 29, 40, 103, 152, 181, 187, 193, 195, 196, 205, 214, 311, 328, 330, 340, 355, 366, 369, 407 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
160	abolishes mapk9 interaction.
161	abolishes mapk9 interaction.
704	no effect on kns2 binding.
709	abolishes kns2 binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 203 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_MAP_KINASE_ACTIVITY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, KEGG_MAPK_SIGNALING_PATHWAY, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_VESICLE_MEDIATED_TRANSPORT, ATGCAGT_MIR217, GOBP_NEGATIVE_REGULATION_OF_JUN_KINASE_ACTIVITY, RAMJAUN_APOPTOSIS_BY_TGFB1_VIA_SMAD4_DN

GO Biological Process (12): regulation of DNA-templated transcription (GO:0006355), JNK cascade (GO:0007254), vesicle-mediated transport (GO:0016192), negative regulation of JUN kinase activity (GO:0043508), regulation of JNK cascade (GO:0046328), positive regulation of JNK cascade (GO:0046330), regulation of CD8-positive, alpha-beta T cell proliferation (GO:2000564), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), MAPK cascade (GO:0000165), signal transduction (GO:0007165), negative regulation of apoptotic process (GO:0043066), negative regulation of JNK cascade (GO:0046329)

GO Molecular Function (8): protein kinase inhibitor activity (GO:0004860), MAP kinase scaffold activity (GO:0005078), JUN kinase binding (GO:0008432), kinesin binding (GO:0019894), mitogen-activated protein kinase kinase binding (GO:0031434), mitogen-activated protein kinase kinase kinase binding (GO:0031435), protein binding (GO:0005515), protein kinase binding (GO:0019901)

GO Cellular Component (18): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), mitochondrial membrane (GO:0031966), neuronal cell body (GO:0043025), dendritic growth cone (GO:0044294), axonal growth cone (GO:0044295), dentate gyrus mossy fiber (GO:0044302), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), neuron projection (GO:0043005)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	4
JNK cascade	3
protein kinase binding	3
intracellular membrane-bounded organelle	3
MAPK cascade	2
cellular process	2
regulation of JNK cascade	2
organelle membrane	2
growth cone	2
neuron projection	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transport	1
JUN kinase activity	1
negative regulation of MAP kinase activity	1
regulation of JUN kinase activity	1
negative regulation of JNK cascade	1
regulation of MAPK cascade	1
positive regulation of MAPK cascade	1
CD8-positive, alpha-beta T cell proliferation	1
regulation of alpha-beta T cell proliferation	1
regulation of CD8-positive, alpha-beta T cell activation	1
intrinsic apoptotic signaling pathway	1
negative regulation of intracellular signal transduction	1
negative regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
intracellular signaling cassette	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of MAPK cascade	1
protein kinase activity	1
kinase inhibitor activity	1
protein kinase regulator activity	1

Protein interactions and networks

STRING

1556 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK8IP1	MAPK8	P45983	993
MAPK8IP1	JUN	P05412	989
MAPK8IP1	KLC1	Q07866	983
MAPK8IP1	MAP2K7	O14733	981
MAPK8IP1	KLC4	Q9NSK0	906
MAPK8IP1	KLC2	Q9H0B6	903
MAPK8IP1	PTPRN	Q16849	901
MAPK8IP1	MAP3K13	O43283	899
MAPK8IP1	INSM1	Q01101	884
MAPK8IP1	KLC3	Q6P597	880
MAPK8IP1	MAPK8IP3	Q9UPT6	860
MAPK8IP1	MAP3K11	Q16584	858
MAPK8IP1	MAPK8IP2	Q13387	814
MAPK8IP1	APP	P05067	804
MAPK8IP1	SPAG9	O60271	790

IntAct

58 interactions, top by confidence:

A	B	Type	Score
MAPK8IP1	APP	psi-mi:“MI:0915”(physical association)	0.780
MAPK8IP1	APP	psi-mi:“MI:0407”(direct interaction)	0.780
MAPK8IP1	MAPK8	psi-mi:“MI:0914”(association)	0.770
MAPK8	MAPK8IP1	psi-mi:“MI:0915”(physical association)	0.770
MAPK8	WDR62	psi-mi:“MI:0914”(association)	0.730
MAP3K7	MAPK8IP1	psi-mi:“MI:0915”(physical association)	0.720
MAPK8IP1	MAP3K7	psi-mi:“MI:0914”(association)	0.720
MAPK8IP3	RCCD1	psi-mi:“MI:0914”(association)	0.640
MAPK8IP1	MAP2K7	psi-mi:“MI:0914”(association)	0.620
MAPK8IP1	MAP2K7	psi-mi:“MI:0915”(physical association)	0.620
ERBB2	MAPK8IP1	psi-mi:“MI:0915”(physical association)	0.590
MAPK8IP1	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.590
MAPK8IP1	HOXC8	psi-mi:“MI:0914”(association)	0.530
MAPK8IP3	DCTN6	psi-mi:“MI:0914”(association)	0.530

BioGRID (110): MAPK8IP1 (Affinity Capture-Western), JUN (Affinity Capture-Western), MAPK8IP1 (Affinity Capture-Western), MAPK8IP1 (Biochemical Activity), TTLL4 (Affinity Capture-MS), MAPK8IP2 (Affinity Capture-MS), ANK3 (Affinity Capture-MS), MAPK8 (Affinity Capture-MS), MAPK9 (Affinity Capture-MS), MAPK8IP1 (Affinity Capture-MS), FEM1B (Affinity Capture-MS), HOXC8 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), SENP5 (Affinity Capture-MS), SETX (Affinity Capture-MS)

ESM2 similar proteins: A0FI79, A1A4I4, A1A5B6, A4D2P6, A6H7I8, F1LXF1, O60346, P11274, P53349, P59672, P70268, Q0QWG9, Q13905, Q3MII6, Q3U0J8, Q504T8, Q50H33, Q5EBH1, Q62865, Q63433, Q69ZT9, Q6NS60, Q6PAJ1, Q6WVG3, Q6ZWB6, Q7Z5H3, Q8BL80, Q8BUP8, Q8BYH7, Q8C190, Q8CGA2, Q8CHE4, Q8N2R8, Q8R554, Q8TE49, Q8TF61, Q8WUA7, Q92625, Q95KI1, Q96CX2

Diamond homologs: A5D8S5, G3V9M2, G5EC32, Q13387, Q9ERE9, Q9R237, Q9UQF2, Q9W0K0, Q9WVI9, A5PMU4, D3ZAR1, O76337, O88888, P0C6S7, P59672, Q32PV0, Q5PQS4, Q5SW96, Q67FQ3, Q7JUY7, Q7Z6G8, Q801G1, Q8BIZ1, Q8C142, Q8K2A1, Q92625, Q9UBP9, A1L1I3, O08919, O35431, O88797, P98078, P98084, Q5RD33, Q99767, Q9Y6R0, Q28E95, Q69ZI1, Q6NRD3, Q71F54

SIGNOR signaling

22 interactions.

A	Effect	B	Mechanism
MAPK9	“up-regulates activity”	MAPK8IP1	phosphorylation
MAPK8IP1	down-regulates	MAP3K12	binding
MAPK8IP1	down-regulates	MAPK8	binding
MAPK8IP1	up-regulates	MAP3K10	binding
SH3RF1	up-regulates	MAPK8IP1	binding
MAPK8IP1	down-regulates	NOTCH1	binding
MAPK8IP1	down-regulates	RBPJ	binding
INPPL1	up-regulates	MAPK8IP1
MAPK8IP1	up-regulates	MAP2K7	binding
MAPK8IP1	down-regulates	MAPK9	binding
MAPK8IP2	up-regulates	MAPK8IP1	binding
MAPK8IP1	down-regulates	MAP4K2	binding
DUSP16	up-regulates	MAPK8IP1	binding
MAPK8	unknown	MAPK8IP1	phosphorylation
MAPK8	“up-regulates activity”	MAPK8IP1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by Interleukins	5	21.4×	4e-05
Cytokine Signaling in Immune system	6	16.3×	3e-05
Infectious disease	5	8.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

136 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	112
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2426467	NC_000011.9:g.(?45827353)(47804770_?)del	Pathogenic

SpliceAI

1797 predictions. Top by Δscore:

Variant	Effect	Δscore
11:45898083:A:AG	acceptor_gain	1.0000
11:45898084:G:GG	acceptor_gain	1.0000
11:45898188:CGGGT:C	donor_loss	1.0000
11:45898189:GG:G	donor_gain	1.0000
11:45898190:GG:G	donor_gain	1.0000
11:45898190:GGT:G	donor_loss	1.0000
11:45898191:G:A	donor_loss	1.0000
11:45898192:T:A	donor_loss	1.0000
11:45903185:G:GG	donor_gain	1.0000
11:45903977:T:TA	acceptor_gain	1.0000
11:45903980:T:A	acceptor_gain	1.0000
11:45903984:GACA:G	acceptor_loss	1.0000
11:45903985:ACAG:A	acceptor_loss	1.0000
11:45903988:GGTTT:G	acceptor_gain	1.0000
11:45904158:GCAG:G	donor_gain	1.0000
11:45904159:CAGG:C	donor_loss	1.0000
11:45904161:GGTAG:G	donor_loss	1.0000
11:45904162:G:C	donor_loss	1.0000
11:45904162:G:GG	donor_gain	1.0000
11:45904712:CTGTA:C	acceptor_loss	1.0000
11:45904713:TGTA:T	acceptor_loss	1.0000
11:45904714:GTAGA:G	acceptor_loss	1.0000
11:45904716:A:AG	acceptor_gain	1.0000
11:45904717:G:GA	acceptor_gain	1.0000
11:45904717:G:GC	acceptor_loss	1.0000
11:45904717:GA:G	acceptor_gain	1.0000
11:45904717:GATT:G	acceptor_gain	1.0000
11:45904826:G:GT	donor_gain	1.0000
11:45905042:G:GG	donor_gain	1.0000
11:45905146:TGCA:T	acceptor_loss	1.0000

AlphaMissense

4626 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:45902915:T:C	L383P	1.000
11:45904499:T:C	F571L	1.000
11:45904500:T:C	F571S	1.000
11:45904500:T:G	F571C	1.000
11:45904501:C:A	F571L	1.000
11:45904501:C:G	F571L	1.000
11:45904503:T:A	L572Q	1.000
11:45904503:T:C	L572P	1.000
11:45904505:G:C	G573R	1.000
11:45904506:G:A	G573D	1.000
11:45904506:G:T	G573V	1.000
11:45904512:T:A	V575D	1.000
11:45904518:T:A	V577D	1.000
11:45904532:G:C	G582R	1.000
11:45904533:G:T	G582V	1.000
11:45904545:T:A	L586H	1.000
11:45904545:T:C	L586P	1.000
11:45904553:G:C	A589P	1.000
11:45904554:C:A	A589D	1.000
11:45904557:T:A	M590K	1.000
11:45904557:T:C	M590T	1.000
11:45904557:T:G	M590R	1.000
11:45904722:C:A	A594D	1.000
11:45904773:T:C	L611P	1.000
11:45904790:G:C	G617R	1.000
11:45904992:T:C	F639L	1.000
11:45904993:T:C	F639S	1.000
11:45904994:C:A	F639L	1.000
11:45904994:C:G	F639L	1.000
11:45904999:T:C	L641S	1.000

dbSNP variants (sampled 300 via entrez): RS1000013446 (11:45885785 C>G,T), RS1000053291 (11:45886148 T>C), RS1000212428 (11:45901271 C>T), RS1000265916 (11:45891717 G>C), RS1000268723 (11:45897985 T>C), RS1000340434 (11:45897710 C>T), RS1000447 (11:45892493 G>A), RS1000624176 (11:45896814 C>G), RS1000655199 (11:45896580 C>A,T), RS1000895136 (11:45903659 G>A), RS1000896828 (11:45891029 C>A), RS1001007941 (11:45898132 C>G,T), RS1001216321 (11:45893232 C>G,T), RS1001266764 (11:45899799 G>T), RS1001340432 (11:45899464 C>T)

Disease associations

OMIM: gene MIM:604641 | disease phenotypes: MIM:266265, MIM:125853

GenCC curated gene-disease

Disease	Classification	Inheritance
diabetes mellitus, noninsulin-dependent	Limited	Autosomal dominant
type 2 diabetes mellitus	Limited	Autosomal dominant

Mondo (3): leukocyte adhesion deficiency type II (MONDO:0009953), type 2 diabetes mellitus (MONDO:0005148), (MONDO:0007455)

Orphanet (2): Leukocyte adhesion deficiency (Orphanet:2968), Leukocyte adhesion deficiency type II (Orphanet:99843)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000855	Insulin resistance
HP:0003584	Late onset
HP:0005978	Type II diabetes mellitus
HP:0031819	Increased waist to hip ratio

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002115_15	Axial length	2.000000e-06
GCST007825_1	Alzheimer’s disease or fasting glucose levels (pleiotropy)	2.000000e-13
GCST010002_237	Refractive error	1.000000e-10
GCST010242_412	HDL cholesterol levels	1.000000e-23

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005318	axial length measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
C535755	Congenital disorder of glycosylation, type 2C (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction, increases expression	1
Cannabidiol	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	increases reaction, increases expression	1
Smoke	increases abundance, increases expression	1
T-2 Toxin	increases expression	1
Valproic Acid	increases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3AR	Abcam HEK293T MAPK8IP1 KO	Transformed cell line	Female
CVCL_D7UN	Ubigene A-549 MAPK8IP1 KO	Cancer cell line	Male
CVCL_D9JR	Ubigene HEK293 MAPK8IP1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus