MAPK8IP3

Summary

MAPK8IP3 (mitogen-activated protein kinase 8 interacting protein 3, HGNC:6884) is a protein-coding gene on chromosome 16p13.3, encoding C-Jun-amino-terminal kinase-interacting protein 3 (Q9UPT6). 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.

The protein encoded by this gene shares similarity with the product of Drosophila syd gene, required for the functional interaction of kinesin I with axonal cargo. Studies of the similar gene in mouse suggested that this protein may interact with, and regulate the activity of numerous protein kinases of the JNK signaling pathway, and thus function as a scaffold protein in neuronal cells. The C. elegans counterpart of this gene is found to regulate synaptic vesicle transport possibly by integrating JNK signaling and kinesin-1 transport. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.

Source: NCBI Gene 23162 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with or without variable brain abnormalities; NEDBA (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 584 total — 5 pathogenic, 11 likely-pathogenic
• MANE Select transcript: NM_001318852

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6884
Approved symbol	MAPK8IP3
Name	mitogen-activated protein kinase 8 interacting protein 3
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1066, JSAP1, JIP3, syd
Ensembl gene	ENSG00000138834
Ensembl biotype	protein_coding
OMIM	605431
Entrez	23162

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 11 retained_intron, 5 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000250894, ENST00000356010, ENST00000561765, ENST00000561949, ENST00000562042, ENST00000563868, ENST00000564098, ENST00000564868, ENST00000566064, ENST00000566589, ENST00000567352, ENST00000567849, ENST00000568271, ENST00000568774, ENST00000570131, ENST00000610761, ENST00000673691, ENST00000685565, ENST00000685674

RefSeq mRNA: 3 — MANE Select: NM_001318852 NM_001040439, NM_001318852, NM_015133

CCDS: CCDS10442, CCDS45379, CCDS81929

Canonical transcript exons

ENST00000610761 — 32 exons

Exon	Start	End
ENSE00000683477	1768069	1768107
ENSE00000683478	1767805	1767918
ENSE00000683488	1766220	1766409
ENSE00000892272	1765013	1765178
ENSE00001163461	1765960	1766142
ENSE00001163527	1761224	1761305
ENSE00001528499	1767149	1767297
ENSE00001699405	1758978	1758995
ENSE00003468004	1766904	1766971
ENSE00003481120	1763657	1763783
ENSE00003484931	1766723	1766803
ENSE00003486290	1767564	1767735
ENSE00003491877	1729487	1729578
ENSE00003529167	1768477	1768626
ENSE00003531268	1764115	1764210
ENSE00003538811	1748602	1748720
ENSE00003558824	1762836	1763006
ENSE00003572688	1766529	1766648
ENSE00003576282	1762351	1762481
ENSE00003576779	1748244	1748346
ENSE00003600994	1768199	1768378
ENSE00003604312	1759958	1760015
ENSE00003605288	1729138	1729208
ENSE00003614628	1762675	1762731
ENSE00003617377	1764301	1764459
ENSE00003625585	1758148	1758159
ENSE00003661874	1760380	1760532
ENSE00003667431	1724557	1724677
ENSE00003690613	1747029	1747275
ENSE00003727809	1768703	1770351
ENSE00003746218	1743332	1743476
ENSE00003747541	1706195	1706657

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.4418 / max 751.6970, expressed in 1794 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152120	25.8691	1794
152121	0.3991	186
152127	0.0671	8
152125	0.0542	12
152126	0.0261	10
152122	0.0134	3
152124	0.0127	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.30	gold quality
cerebellar hemisphere	UBERON:0002245	99.21	gold quality
cerebellar cortex	UBERON:0002129	99.19	gold quality
cerebellum	UBERON:0002037	98.62	gold quality
right frontal lobe	UBERON:0002810	98.18	gold quality
adenohypophysis	UBERON:0002196	98.03	gold quality
prefrontal cortex	UBERON:0000451	97.90	gold quality
granulocyte	CL:0000094	97.49	gold quality
pituitary gland	UBERON:0000007	97.39	gold quality
sural nerve	UBERON:0015488	97.12	gold quality
left ovary	UBERON:0002119	97.08	gold quality
cingulate cortex	UBERON:0003027	97.08	gold quality
anterior cingulate cortex	UBERON:0009835	97.05	gold quality
right ovary	UBERON:0002118	96.98	gold quality
metanephros cortex	UBERON:0010533	96.93	gold quality
frontal cortex	UBERON:0001870	96.75	gold quality
frontal lobe	UBERON:0016525	96.74	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.71	gold quality
cortical plate	UBERON:0005343	96.68	gold quality
neocortex	UBERON:0001950	96.54	gold quality
right lobe of thyroid gland	UBERON:0001119	96.51	gold quality
mucosa of stomach	UBERON:0001199	96.46	gold quality
right uterine tube	UBERON:0001302	96.45	gold quality
olfactory bulb	UBERON:0002264	96.45	gold quality
left lobe of thyroid gland	UBERON:0001120	96.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.40	gold quality
nucleus accumbens	UBERON:0001882	96.37	gold quality
nerve	UBERON:0001021	96.30	gold quality
tibial nerve	UBERON:0001323	96.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.30	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.43
E-CURD-10	no	113.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

128 targeting MAPK8IP3, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-556-3P	99.74	68.75	1203

Literature-anchored findings (GeneRIF, showing 23)

• demonstration that JSAP1 bound ASK1 and enhanced ASK1- and H2O2-induced JNK activity (PMID:12189133)
• Pressure application of 160 mmHg for 3 h produced cell proliferation and activated ERK and c-JUN N-terminal kinase (PMID:15532711)
• 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)
• JSAP1.FAK complex functions cooperatively as a scaffold for the JNK signaling pathway and regulator of cell migration on FN (PMID:16141199)
• Upon UVB-induced stress in keratinocytes, ROCK1 was activated, bound to JIP-3, and activated the JNK pathway (PMID:19036714)
• Cyclic mechanical strain impairs signaling of cell migration after injury via a pathway that involves FAK-JIP3-JNK. (PMID:19574423)
• Expression of constitutively active PI3K stimulated translocation of Tiam1 to the membrane, increased Rac1 activity, and increased wound healing of airway epithelial cells. Increased Rac1 activity resulted in increased phosphorylation of JNK1. (PMID:20018857)
• This study demonistrated that JIP3 mediates TrkB axonal anterograde transport and enhances BDNF signaling by directly bridging TrkB with kinesin-1. (PMID:21775604)
• The results of this study finding suggested that a model by which the self-assembly of SYD-2/Liprin-alpha proteins mediated by the coiled-coil LH1 domain is one of the key steps to the accumulation of presynaptic components at nascent synaptic junctions (PMID:22072677)
• Results demonstrated the increased expression of JIP3 in the temporal neocortex of TLE patients and in the experimental model of epileptic seizures (PMID:26002316)
• JSAP1 and JLP play critical roles in kinesin-1-dependent axonal transport (PMID:26320416)
• The crystal structure of an N-terminally truncated form of LZII of JIP3 alone shows an unexpected antiparallel arrangement. (PMID:26919523)
• JIP3 was highly expressed in hearts with hypertrophic cardiomyopathy. The findings indicated that blockage of JIP3 could alleviate cardiac hypertrophy via inactivating JNK pathway, and thus might be a promising strategy to prevent pathological cardiac hypertrophy. (PMID:29604277)
• implication of de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies (PMID:30612693)
• MAPK8IP3 variants cause a neurodevelopmental disease which includes spastic diplegia, intellectual disability, cerebral atrophy and corpus callosum hypoplasia. (PMID:30945334)
• in HT1080 cells, a human fibrosarcoma cell line, a requirement for microtubules, dynein, the JIP3 microtubule motor scaffold protein, and Arf6, a JIP3 interacting protein, for the formation and inward movement of the macropinosome, is reported. (PMID:30969891)
• Structural characterization of the RH1-LZI tandem of JIP3/4 highlights RH1 domains as a cytoskeletal motor-binding motif. (PMID:31690808)
• Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons. (PMID:33788575)
• Sequential dynein effectors regulate axonal autophagosome motility in a maturation-dependent pathway. (PMID:34014261)
• JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton. (PMID:35013510)
• JIP3 interacts with dynein and kinesin-1 to regulate bidirectional organelle transport. (PMID:35829703)
• Compound heterozygous variants in MAPK8IP3 were detected in severe congenital hypotonia mimicking lethal spinal muscular atrophy. (PMID:37462082)
• Molecular mechanism of dynein-dynactin complex assembly by LIS1. (PMID:38547289)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapk8ip3	ENSDARG00000062531
mus_musculus	Mapk8ip3	ENSMUSG00000024163
rattus_norvegicus	Mapk8ip3	ENSRNOG00000033568
drosophila_melanogaster	syd	FBGN0024187
caenorhabditis_elegans		WBGENE00006755

Paralogs (1): SPAG9 (ENSG00000008294)

Protein

Protein identifiers

C-Jun-amino-terminal kinase-interacting protein 3 — Q9UPT6 (reviewed: Q9UPT6)

Alternative names: JNK MAP kinase scaffold protein 3, Mitogen-activated protein kinase 8-interacting protein 3

All UniProt accessions (6): A0A087WYG2, A0A669KB35, A0A8I5KWZ2, E9PFH7, Q9UPT6, H3BN91

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. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins. Promotes neuronal axon elongation in a kinesin- and JNK-dependent manner. Activates cofilin at axon tips via local activation of JNK, thereby regulating filopodial dynamics and enhancing axon elongation. Its binding to kinesin heavy chains (KHC), promotes kinesin-1 motility along microtubules and is essential for axon elongation and regeneration. Regulates cortical neuronal migration by mediating NTRK2/TRKB anterograde axonal transport during brain development. Acts as an adapter that bridges the interaction between NTRK2/TRKB and KLC1 and drives NTRK2/TRKB axonal but not dendritic anterograde transport, which is essential for subsequent BDNF-triggered signaling and filopodia formation.

Subunit / interactions. Forms homo- or heterooligomeric complexes. The central region of MAPK8IP3 interacts with the C-terminal of MAPK8IP2 but not MAPK8IP1. Binds specific components of the JNK signaling pathway namely MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3 to the N-terminal region, MAP2K4/MKK4 and MAP2K7/MKK7 to the central region and MAP3K11 to the C-terminal region. Binds the TPR motif-containing C-terminal of kinesin light chain, KLC1. Pre-assembled MAPK8IP1 scaffolding complexes are then transported as a cargo of kinesin, to the required subcellular location. Interacts with ROCK1 and this interaction is enhanced by ultraviolet-B (UVB) radiation. Interacts with SH3RF2. Interacts with NTRK2/TRKB and NTRK3/TRKC.

Subcellular location. Cytoplasm. Golgi apparatus. Cytoplasmic vesicle. Cell projection. Growth cone. Axon. Dendrite. Perinuclear region.

Post-translational modifications. Phosphorylation by ROCK1 is crucial for the recruitment of JNK.

Disease relevance. Neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) [MIM:618443] A disorder characterized by global developmental delay, impaired intellectual development, delayed walking, poor or absent speech, and variable brain anomalies including perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the JIP scaffold family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UPT6-1	1	yes
Q9UPT6-2	2

RefSeq proteins (3): NP_001035529, NP_001305781, NP_055948 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR032486	JIP_LZII	Domain
IPR034743	RH1	Domain
IPR034744	RH2	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR039911	JIP3/JIP4	Family

Pfam: PF09744, PF16471, PF19056

UniProt features (43 total): region of interest 9, sequence variant 9, modified residue 8, compositionally biased region 5, helix 4, domain 2, coiled-coil region 2, splice variant 2, chain 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4PXJ	X-RAY DIFFRACTION	2.06
8PR4	ELECTRON MICROSCOPY	3.5
8PR2	ELECTRON MICROSCOPY	3.8
8PR3	ELECTRON MICROSCOPY	3.9
8PTK	ELECTRON MICROSCOPY	10

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UPT6-F1	63.19	0.23

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 (8): 265, 275, 286, 314, 364, 365, 602, 676

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 359 (showing top): GCM_MAP4K4, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, KEGG_MAPK_SIGNALING_PATHWAY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGENERATION, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, GOBP_NEUROGENESIS, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, SCIBETTA_KDM5B_TARGETS_UP, GOBP_RESPONSE_TO_AXON_INJURY

GO Biological Process (20): vesicle-mediated transport (GO:0016192), axon regeneration (GO:0031103), negative regulation of apoptotic process (GO:0043066), regulation of JNK cascade (GO:0046328), positive regulation of JNK cascade (GO:0046330), protein stabilization (GO:0050821), axon development (GO:0061564), anterograde axonal protein transport (GO:0099641), MAPK cascade (GO:0000165), in utero embryonic development (GO:0001701), JNK cascade (GO:0007254), axon guidance (GO:0007411), respiratory gaseous exchange by respiratory system (GO:0007585), intracellular protein localization (GO:0008104), post-embryonic development (GO:0009791), regulation of gene expression (GO:0010468), forebrain development (GO:0030900), lung alveolus development (GO:0048286), lung morphogenesis (GO:0060425), positive regulation of neuron migration (GO:2001224)

GO Molecular Function (7): MAP kinase scaffold activity (GO:0005078), JUN kinase binding (GO:0008432), kinesin binding (GO:0019894), signaling receptor complex adaptor activity (GO:0030159), protein binding (GO:0005515), mitogen-activated protein kinase kinase binding (GO:0031434), mitogen-activated protein kinase kinase kinase binding (GO:0031435)

GO Cellular Component (14): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), axon (GO:0030424), dendrite (GO:0030425), growth cone (GO:0030426), cytoplasmic vesicle (GO:0031410), cell body (GO:0044297), perinuclear region of cytoplasm (GO:0048471), axon cytoplasm (GO:1904115), smooth endoplasmic reticulum (GO:0005790), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), axolemma (GO:0030673), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein kinase binding	3
cytoplasm	3
JNK cascade	2
MAPK cascade	2
multicellular organismal process	2
anatomical structure development	2
lung development	2
signaling adaptor activity	2
neuron projection	2
transport	1
cellular process	1
neuron projection regeneration	1
response to axon injury	1
axon development	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
regulation of MAPK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
regulation of protein stability	1
neuron projection development	1
anterograde axonal transport	1
axo-dendritic protein transport	1
protein localization to presynapse	1
intracellular signaling cassette	1
chordate embryonic development	1
axonogenesis	1
neuron projection guidance	1
macromolecule localization	1
multicellular organism development	1
gene expression	1
regulation of macromolecule biosynthetic process	1
brain development	1
animal organ morphogenesis	1
neuron migration	1
positive regulation of cell migration	1
regulation of neuron migration	1
mitogen-activated protein kinase binding	1

Protein interactions and networks

STRING

1464 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK8IP3	KLC1	Q07866	976
MAPK8IP3	KLC2	Q9H0B6	943
MAPK8IP3	KLC3	Q6P597	935
MAPK8IP3	KLC4	Q9NSK0	924
MAPK8IP3	DCTN1	Q14203	875
MAPK8IP3	MAPK8IP1	Q9UQF2	860
MAPK8IP3	ARF6	P26438	856
MAPK8IP3	MAP2K7	O14733	848
MAPK8IP3	MAPK8IP2	Q13387	830
MAPK8IP3	GRIP1	Q9Y3R0	783
MAPK8IP3	JUN	P05412	771
MAPK8IP3	MAP2K4	P45985	714
MAPK8IP3	TLR4	O00206	654
MAPK8IP3	PPFIA3	O75145	649
MAPK8IP3	PICK1	Q9NRD5	638

IntAct

55 interactions, top by confidence:

A	B	Type	Score
LDLRAP1	MAPK8IP3	psi-mi:“MI:0915”(physical association)	0.720
MAPK8IP3	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.720
SULT4A1	MAPK8IP3	psi-mi:“MI:0915”(physical association)	0.670
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
MAPK8IP3	RCCD1	psi-mi:“MI:0914”(association)	0.640
RAD51D	MAPK8IP3	psi-mi:“MI:0915”(physical association)	0.560
ZNF575	MAPK8IP3	psi-mi:“MI:0915”(physical association)	0.560
KLC1	MAPK8IP3	psi-mi:“MI:0915”(physical association)	0.560
MAPK8IP3	DCTN6	psi-mi:“MI:0914”(association)	0.530
AKR1C2	AKR1C3	psi-mi:“MI:0914”(association)	0.530
MAPK8IP3	RAB8A	psi-mi:“MI:0915”(physical association)	0.400
MAPK8IP3	RAB10	psi-mi:“MI:0915”(physical association)	0.400
MAPK8IP3	FXR1	psi-mi:“MI:0915”(physical association)	0.370
MAPK8IP3	RAD51	psi-mi:“MI:0915”(physical association)	0.370
RCCD1	ZNF609	psi-mi:“MI:0914”(association)	0.350
SMCO1	SPAG9	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CEP63	CIBAR1	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
MAPK8IP3	SHTN1	psi-mi:“MI:0914”(association)	0.350
SULT4A1	SULT2B1	psi-mi:“MI:0914”(association)	0.350
FGF14	ANKRD28	psi-mi:“MI:0914”(association)	0.350

BioGRID (112): MAPK8IP3 (Co-fractionation), MAPK8IP3 (Affinity Capture-MS), MAPK8IP3 (Two-hybrid), KLC1 (Two-hybrid), MAPK8IP2 (Affinity Capture-MS), TNKS2 (Affinity Capture-MS), MAPK8IP1 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), MAPK8IP3 (Affinity Capture-MS), MAPK8IP3 (Affinity Capture-MS), TNKS (Affinity Capture-MS), DCTN6 (Affinity Capture-MS), ACTR10 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), DCTN4 (Affinity Capture-MS)

ESM2 similar proteins: A0A088MLT8, A2AQ25, B3KU38, B5DF41, E9PSK7, O15079, O35274, P0DPB3, P0DPB4, P12755, P49140, P85299, Q0D2I5, Q14DQ1, Q1LY51, Q3B7M3, Q3SYW5, Q4KMA0, Q4R3X1, Q50H33, Q5F3L9, Q5FVG6, Q5RD40, Q5XKK7, Q60698, Q6ZNC4, Q6ZUS6, Q6ZWB6, Q80U23, Q80U62, Q80XA6, Q812A5, Q86YI8, Q8BXL9, Q8K2W6, Q8ND83, Q8NFH8, Q8QFX1, Q8TEK3, Q924W7

Diamond homologs: A2AWP8, E9PSK7, O15013, P34609, P52734, P98174, Q07139, Q1ZXH8, Q29RM4, Q58A65, Q5R5M3, Q8C033, Q9ESN9, Q9H8V3, Q9HCE6, Q9UPT6, O60271, Q29EP6, Q80U35, Q9GQF1

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
MAPK10	up-regulates	MAPK8IP3	phosphorylation
MAPK8	up-regulates	MAPK8IP3	phosphorylation
MAPK8IP3	up-regulates	MAPK10	binding
MAPK8IP3	up-regulates	MAPK8	binding
MAPK8IP3	up-regulates	MAPK9	binding
MAPK9	up-regulates	MAPK8IP3	phosphorylation
ROCK1	up-regulates	MAPK8IP3	phosphorylation
MAPK8IP3	up-regulates	JNK	binding
JNK	up-regulates	MAPK8IP3	phosphorylation
MAPK8IP3	up-regulates	MAP2K4	binding
MAPK8IP3	up-regulates	MAP3K1	binding
MAPK8IP3	up-regulates	MAP2K7	binding
MAPK8IP3	up-regulates	MAP3K11	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	11
Uncertain significance	358
Likely benign	135
Benign	23

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
2442239	NM_001318852.2(MAPK8IP3):c.1363G>T (p.Glu455Ter)	Pathogenic
3366632	NM_001318852.2(MAPK8IP3):c.1402C>T (p.Gln468Ter)	Pathogenic
3383490	NM_001318852.2(MAPK8IP3):c.3334_3335del (p.Leu1112fs)	Pathogenic
4819772	NM_001318852.2(MAPK8IP3):c.2924del (p.Gly975fs)	Pathogenic
986035	NM_001318852.2(MAPK8IP3):c.2919G>A (p.Trp973Ter)	Pathogenic
1184954	NM_001318852.2(MAPK8IP3):c.2121+1dup	Likely pathogenic
2575910	NM_001318852.2(MAPK8IP3):c.167T>A (p.Met56Lys)	Likely pathogenic
3256795	NM_001318852.2(MAPK8IP3):c.2122-1G>A	Likely pathogenic
3901519	NM_001318852.2(MAPK8IP3):c.2630-2_2630-1del	Likely pathogenic
4056600	NM_001318852.2(MAPK8IP3):c.748-2A>C	Likely pathogenic
4527158	NC_000016.10:g.1767914AG[2]	Likely pathogenic
598741	NM_001318852.2(MAPK8IP3):c.111C>G (p.Tyr37Ter)	Likely pathogenic
632561	NM_001318852.2(MAPK8IP3):c.65del (p.Gly22fs)	Likely pathogenic
632563	NM_001318852.2(MAPK8IP3):c.1334T>C (p.Leu445Pro)	Likely pathogenic
805861	NM_001318852.2(MAPK8IP3):c.79G>T (p.Glu27Ter)	Likely pathogenic
916591	NM_001318852.2(MAPK8IP3):c.1385A>G (p.Glu462Gly)	Likely pathogenic

SpliceAI

5422 predictions. Top by Δscore:

Variant	Effect	Δscore
16:1724549:A:AG	acceptor_gain	1.0000
16:1724549:AT:A	acceptor_gain	1.0000
16:1724550:T:G	acceptor_gain	1.0000
16:1724550:T:TA	acceptor_gain	1.0000
16:1724552:CACA:C	acceptor_loss	1.0000
16:1724553:A:AG	acceptor_gain	1.0000
16:1724554:C:G	acceptor_gain	1.0000
16:1724554:CA:C	acceptor_loss	1.0000
16:1724555:A:AG	acceptor_gain	1.0000
16:1724556:G:GA	acceptor_gain	1.0000
16:1724556:GA:G	acceptor_gain	1.0000
16:1724556:GAA:G	acceptor_gain	1.0000
16:1724556:GAAA:G	acceptor_gain	1.0000
16:1724556:GAAAT:G	acceptor_gain	1.0000
16:1724673:TCAGA:T	donor_gain	1.0000
16:1724674:CAGA:C	donor_gain	1.0000
16:1724674:CAGAG:C	donor_loss	1.0000
16:1724675:AGA:A	donor_gain	1.0000
16:1724676:GA:G	donor_gain	1.0000
16:1724676:GAG:G	donor_gain	1.0000
16:1724676:GAGTA:G	donor_loss	1.0000
16:1724677:AG:A	donor_loss	1.0000
16:1724678:G:GG	donor_gain	1.0000
16:1724678:GTAAG:G	donor_loss	1.0000
16:1724679:T:TC	donor_loss	1.0000
16:1729136:A:AG	acceptor_gain	1.0000
16:1729137:G:GG	acceptor_gain	1.0000
16:1729482:CGCA:C	acceptor_loss	1.0000
16:1729484:CA:C	acceptor_loss	1.0000
16:1729485:A:AC	acceptor_loss	1.0000

AlphaMissense

8791 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:1706446:T:A	I36N	1.000
16:1706458:T:C	F40S	1.000
16:1706467:T:C	L43P	1.000
16:1706494:T:A	V52D	1.000
16:1706503:T:A	L55H	1.000
16:1706503:T:C	L55P	1.000
16:1706527:T:C	L63P	1.000
16:1706536:T:C	L66P	1.000
16:1706584:T:C	L82P	1.000
16:1706587:T:C	L83P	1.000
16:1706608:T:C	L90P	1.000
16:1706626:G:C	R96P	1.000
16:1729198:G:C	R167P	1.000
16:1759982:T:C	L423P	1.000
16:1760003:T:C	L430P	1.000
16:1760409:T:C	L444P	1.000
16:1762399:G:C	A529P	1.000
16:1762409:T:A	L532H	1.000
16:1762409:T:C	L532P	1.000
16:1762418:G:C	R535P	1.000
16:1762431:G:C	K539N	1.000
16:1762431:G:T	K539N	1.000
16:1762439:T:C	L542P	1.000
16:1762448:T:C	L545P	1.000
16:1762456:G:C	A548P	1.000
16:1762465:T:A	W551R	1.000
16:1762465:T:C	W551R	1.000
16:1763757:T:A	W666R	1.000
16:1763757:T:C	W666R	1.000
16:1763759:G:C	W666C	1.000

dbSNP variants (sampled 300 via entrez): RS1000005360 (16:1741098 G>A), RS1000060130 (16:1732816 C>T), RS1000080954 (16:1770394 G>A,C), RS1000086819 (16:1748727 G>A), RS1000098190 (16:1740990 A>C), RS1000170559 (16:1766594 C>G,T), RS1000186937 (16:1718823 G>C,T), RS1000196826 (16:1718539 A>G), RS1000214032 (16:1762785 G>A,T), RS1000238193 (16:1754889 G>A,C), RS1000254151 (16:1759621 G>A), RS1000401536 (16:1750519 G>A,C), RS1000412903 (16:1750376 C>T), RS1000437713 (16:1770124 C>A,G,T), RS1000438922 (16:1735639 A>C,G,T)

Disease associations

OMIM: gene MIM:605431 | disease phenotypes: MIM:618443

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with or without variable brain abnormalities; NEDBA	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neurodevelopmental disorder with or without variable brain abnormalities; NEDBA	Definitive	AD

Mondo (3): neurodevelopmental disorder with or without variable brain abnormalities; NEDBA (MONDO:0032755), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005580_103	Intraocular pressure	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, affects methylation, decreases expression	5
Tobacco Smoke Pollution	decreases expression, decreases methylation, increases methylation	3
cobaltous chloride	increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Arsenic	increases abundance, increases expression, affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
dicrotophos	increases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
pyrimidin-2-one beta-ribofuranoside	increases expression	1
sodium arsenate	increases abundance, increases expression	1
arsenite	affects binding, decreases reaction	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
LDN 193189	increases expression, affects cotreatment	1
Acetaminophen	increases expression	1
Glyphosate	increases expression	1
Caffeine	decreases phosphorylation	1
Cannabinoids	affects methylation, increases abundance	1
Chelating Agents	affects binding, decreases expression	1
Cisplatin	decreases expression	1
Copper	affects binding, decreases expression	1
DDT	increases expression	1
Ozone	affects expression, increases abundance	1
Rotenone	decreases expression	1

Cellosaurus cell lines

6 cell lines: 4 induced pluripotent stem cell, 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6WT	GM29256	Induced pluripotent stem cell	Male
CVCL_D6WU	GM29257	Induced pluripotent stem cell	Male
CVCL_D6WV	GM29270	Induced pluripotent stem cell	Male
CVCL_D6WW	GM29271	Induced pluripotent stem cell	Male
CVCL_D7UP	Ubigene A-549 MAPK8IP3 KO	Cancer cell line	Male
CVCL_D9JT	Ubigene HEK293 MAPK8IP3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice