Q9UQF2 (JIP1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
C-Jun-amino-terminal kinase-interacting protein 1
Short name=JIP-1
Short name=JNK-interacting protein 1

Alternative name(s):
Islet-brain 1
Short name=IB-1
JNK MAP kinase scaffold protein 1
Mitogen-activated protein kinase 8-interacting protein 1

Gene names

Name:	MAPK8IP1
Synonyms:	IB1, JIP1, PRKM8IP

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	711 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

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 By similarity. Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.
Subunit structure	Forms homo- or heterooligomeric complexes. Binds specific components of the JNK signaling pathway namely, MAPK8, MAPK9, MAPK10, MAPKK7, MLK2, MLK3, MAP3K12 and MAP3K13. 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 By similarity. Interacts with MAP3K7. Interacts with isoform 1 and isoform 2 of VRK2. Ref.4 Ref.5 Ref.6 Ref.7 Ref.13 Ref.14
Subcellular location	Cytoplasm By similarity. Cytoplasm › perinuclear region By similarity. Nucleus By similarity. Endoplasmic reticulum membrane. Mitochondrion membrane. Note: Accumulates in cell surface projections. Under certain stress conditions, translocates to the perinuclear region of neurons. In insulin-secreting cells, detected in both the cytoplasm and nucleus By similarity. Ref.4 Ref.14
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.
Domain	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 By similarity.
Post-translational modification	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. Ref.8 Ref.12 Ref.14 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. Ref.10
Involvement in disease	Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own 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. Note: The disease may be caused by mutations affecting the gene represented in this entry. Ref.15
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.
Sequence similarities	Belongs to the JIP scaffold family. Contains 1 PID domain. Contains 1 SH3 domain.

Ontologies

Keywords
Cellular component	Cytoplasm Endoplasmic reticulum Membrane Mitochondrion Nucleus
Coding sequence diversity	Polymorphism
Disease	Diabetes mellitus Disease mutation
Domain	Repeat SH3 domain
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	JUN phosphorylation Inferred from electronic annotation. Source: Compara negative regulation of JNK cascade Inferred from electronic annotation. Source: Compara negative regulation of JUN kinase activity Inferred from electronic annotation. Source: Compara negative regulation of apoptotic process Inferred from electronic annotation. Source: Compara regulation of JNK cascade Inferred from sequence or structural similarity. Source: UniProtKB regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: Compara vesicle-mediated transport Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	axonal growth cone Inferred from electronic annotation. Source: Compara cell body Inferred from electronic annotation. Source: Compara cytoplasm Inferred from direct assay Ref.4. Source: UniProtKB cytosol Inferred from electronic annotation. Source: Compara dendritic growth cone Inferred from electronic annotation. Source: Compara dentate gyrus mossy fiber Inferred from electronic annotation. Source: Compara endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrial membrane Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell perinuclear region of cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell synapse Inferred from electronic annotation. Source: Compara
Molecular_function	protein kinase inhibitor activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APP	P05067	4	EBI-78404,EBI-77613
App	P12023	2	EBI-78404,EBI-78814	From a different organism.
MAP3K7	O43318	10	EBI-78404,EBI-358684

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 711	711	C-Jun-amino-terminal kinase-interacting protein 1		PRO_0000220628
Regions
	Domain	488 – 549	62	SH3
	Domain	561 – 700	140	PID
	Region	127 – 285	159	JNK-binding domain (JBD)
	Region	157 – 176	20	Minimal inhibitory domain (MID)
	Region	283 – 471	189	Interaction with MAP3K7
	Region	471 – 660	190	Interaction with VRK2
	Motif	353 – 360	8	D-box 1
	Motif	364 – 372	9	D-box 2
	Compositional bias	42 – 48	7	Asp/Glu-rich (acidic)
	Compositional bias	79 – 84	6	Poly-Gly
	Compositional bias	107 – 116	10	Asp/Glu-rich (acidic)
	Compositional bias	331 – 334	4	Poly-Glu
	Compositional bias	359 – 363	5	Poly-Pro
Amino acid modifications
	Modified residue	40	1	Phosphoserine Ref.12
	Modified residue	103	1	Phosphothreonine; by MAPK8, MAPK9 and MAPK10 Ref.8
	Modified residue	152	1	Phosphoserine
	Modified residue	181	1	Phosphoserine Ref.12
	Modified residue	187	1	Phosphoserine Ref.12
	Modified residue	193	1	Phosphoserine Ref.12
	Modified residue	195	1	Phosphoserine Ref.12
	Modified residue	196	1	Phosphoserine Ref.12
	Modified residue	205	1	Phosphothreonine; by MAPK8, MAPK9 and MAPK10 Ref.8
	Modified residue	214	1	Phosphoserine Ref.12
	Modified residue	311	1	Phosphoserine Ref.12
	Modified residue	328	1	Phosphoserine Ref.12
	Modified residue	330	1	Phosphoserine Ref.12
	Modified residue	340	1	Phosphoserine Ref.12
	Modified residue	355	1	Phosphoserine Ref.12
	Modified residue	366	1	Phosphoserine Ref.12
	Modified residue	369	1	Phosphoserine Ref.12
	Modified residue	407	1	Phosphoserine Ref.12
	Modified residue	409	1	Phosphoserine Ref.12
	Modified residue	411	1	Phosphothreonine Ref.12
	Modified residue	444	1	Phosphoserine Ref.12
	Modified residue	447	1	Phosphoserine Ref.12
	Modified residue	448	1	Phosphothreonine Ref.12
	Modified residue	469	1	Phosphoserine Ref.12
	Modified residue	471	1	Phosphoserine Ref.12
	Modified residue	472	1	Phosphoserine Ref.12
	Modified residue	473	1	Phosphoserine Ref.12
Natural variations
	Natural variant	59	1	S → N in NIDDM. Ref.15		VAR_012243
	Natural variant	322	1	A → V. Corresponds to variant rs34420676 [ dbSNP | Ensembl ].		VAR_049664
	Natural variant	353	1	R → Q. Corresponds to variant rs12295161 [ dbSNP | Ensembl ].		VAR_049665
Experimental info
	Mutagenesis	160	1	R → G: Abolishes MAPK9 interaction. Ref.8
	Mutagenesis	161	1	P → G: Abolishes MAPK9 interaction. Ref.8
	Mutagenesis	704	1	P → A: No effect on KNS2 binding.
	Mutagenesis	709	1	Y → A: Abolishes KNS2 binding.

Sequences

	Sequence		Length	Mass (Da)
	Q9UQF2 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: 55EA53B30080A751	FASTA	711	77,524
	10 20 30 40 50 60 MAERESGGLG GGAASPPAAS PFLGLHIASP PNFRLTHDIS LEEFEDEDLS EITDECGISL 70 80 90 100 110 120 QCKDTLSLRP PRAGLLSAGG GGAGSRLQAE MLQMDLIDAT GDTPGAEDDE EDDDEERAAR 130 140 150 160 170 180 RPGAGPPKAE SGQEPASRGQ GQSQGQSQGP GSGDTYRPKR PTTLNLFPQV PRSQDTLNNN 190 200 210 220 230 240 SLGKKHSWQD RVSRSSSPLK TGEQTPPHEH ICLSDELPPQ SGPAPTTDRG TSTDSPCRRS 250 260 270 280 290 300 TATQMAPPGG PPAAPPGGRG HSHRDRIHYQ ADVRLEATEE IYLTPVQRPP DAAEPTSAFL 310 320 330 340 350 360 PPTESRMSVS SDPDPAAYPS TAGRPHPSIS EEEEGFDCLS SPERAEPPGG GWRGSLGEPP 370 380 390 400 410 420 PPPRASLSSD TSALSYDSVK YTLVVDEHAQ LELVSLRPCF GDYSDESDSA TVYDNCASVS 430 440 450 460 470 480 SPYESAIGEE YEEAPRPQPP ACLSEDSTPD EPDVHFSKKF LNVFMSGRSR SSSAESFGLF 490 500 510 520 530 540 SCIINGEEQE QTHRAIFRFV PRHEDELELE VDDPLLVELQ AEDYWYEAYN MRTGARGVFP 550 560 570 580 590 600 AYYAIEVTKE PEHMAALAKN SDWVDQFRVK FLGSVQVPYH KGNDVLCAAM QKIATTRRLT 610 620 630 640 650 660 VHFNPPSSCV LEISVRGVKI GVKADDSQEA KGNKCSHFFQ LKNISFCGYH PKNNKYFGFI 670 680 690 700 710 TKHPADHRFA CHVFVSEDST KALAESVGRA FQQFYKQFVE YTCPTEDIYL E

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Genomic organization, fine-mapping, and expression of the human islet-brain 1 (IB1)/C-jun-amino-terminal kinase interacting protein-1 (JIP-1) gene." Mooser V., Maillard A., Bonny C., Steinmann M., Shaw P., Yarnall D.P., Burns D.K., Schorderet D.F., Nicod P., Waeber G. Genomics 55:202-208(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Insulinoma.
[2]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	Yu W., Sarginson J., Gibbs R.A. Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 468-711. Tissue: Brain.
[4]	"Interaction of c-Jun amino-terminal kinase interacting protein-1 with p190 rhoGEF and its localization in differentiated neurons." Meyer D., Liu A., Margolis B. J. Biol. Chem. 274:35113-35118(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ARHGEF28, SUBCELLULAR LOCATION.
[5]	"Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules." Verhey K.J., Meyer D., Deehan R., Blenis J., Schnapp B.J., Rapoport T.A., Margolis B. J. Cell Biol. 152:959-970(2001) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS, INTERACTION WITH KINESIN.
[6]	"Mixed lineage kinase LZK forms a functional signaling complex with JIP-1, a scaffold protein of the c-Jun NH(2)-terminal kinase pathway." Ikeda A., Hasegawa K., Masaki M., Moriguchi T., Nishida E., Kozutsumi Y., Oka S., Kawasaki T. J. Biochem. 130:773-781(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MAP3K13.
[7]	"Interaction of Alzheimer's beta-amyloid precursor family proteins with scaffold proteins of the JNK signaling cascade." Taru H., Iijima K., Hase M., Kirino Y., Yagi Y., Suzuki T. J. Biol. Chem. 277:20070-20078(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH APP.
[8]	"Recruitment of JNK to JIP1 and JNK-dependent JIP1 phosphorylation regulates JNK module dynamics and activation." Nihalani D., Wong H.N., Holzman L.B. J. Biol. Chem. 278:28694-28702(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-103 AND THR-205, MUTAGENESIS OF ARG-160 AND PRO-161.
[9]	"Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death." Bonny C., Oberson A., Negri S., Sauser C., Schorderet D.F. Diabetes 50:77-82(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PEPTIDE INHIBITORS OF JNK.
[10]	"Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1." Allaman-Pillet N., Storling J., Oberson A., Roduit R., Negri S., Sauser C., Nicod P., Beckmann J.S., Schorderet D.F., Mandrup-Poulsen T., Bonny C. J. Biol. Chem. 278:48720-48726(2003) [PubMed] [Europe PMC] [Abstract] Cited for: CALCIUM- AND PROTEASOME-DEPENDENT DEGRADATION.
[11]	"A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia." Borsello T., Clarke P.G., Hirt L., Vercelli A., Repici M., Schorderet D.F., Bogousslavsky J., Bonny C. Nat. Med. 9:1180-1186(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PROTECTION AGAINST EXCITOTOXICITY AND CEREBRAL ISCHEMIA.
[12]	"Hyperphosphorylation of JNK-interacting protein 1, a protein associated with Alzheimer disease." D'Ambrosio C., Arena S., Fulcoli G., Scheinfeld M.H., Zhou D., D'Adamio L., Scaloni A. Mol. Cell. Proteomics 5:97-113(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-40; SER-181; SER-187; SER-193; SER-195; SER-196; SER-214; SER-311; SER-328; SER-330; SER-340; SER-355; SER-366; SER-369; SER-407; SER-409; THR-411; SER-444; SER-447; SER-444; THR-448; SER-469; SER-471; SER-472 AND SER-473.
[13]	"Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1." Blanco S., Santos C., Lazo P.A. Mol. Cell. Biol. 27:7273-7283(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MAP3K7.
[14]	"Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein." Blanco S., Sanz-Garcia M., Santos C.R., Lazo P.A. PLoS ONE 3:E1660-E1660(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH VRK2, PHOSPHORYLATION.
[15]	"The gene, MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes." Waeber G., Delplanque J., Bonny C., Mooser V., Steinmann M., Widmann C., Maillard A., Miklossy J., Dina C., Hani E.H., Vionnet N., Nicod P., Boutin P., Froguel P. Nat. Genet. 24:291-295(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT NIDDM ASN-59.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF074091 mRNA. Translation: AAD20443.1.
CH471064 Genomic DNA. Translation: EAW68027.1.
CH471064 Genomic DNA. Translation: EAW68028.1.
AF007134 mRNA. Translation: AAC19150.1.

IPI

IPI00023133.

RefSeq

NP_005447.1. NM_005456.3.

UniGene

Hs.234249.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2G01	X-ray	3.50	F/G	157-167	[»]
2GMX	X-ray	3.50	F/G	157-167	[»]
2H96	X-ray	3.00	F/G	157-167	[»]
3OXI	X-ray	2.20	J	158-167	[»]
3PTG	X-ray	2.43	J	157-167	[»]
3VUD	X-ray	3.50	F	157-167	[»]
3VUG	X-ray	3.24	F	157-167	[»]
3VUH	X-ray	2.70	F	157-167	[»]
3VUI	X-ray	2.80	F	157-167	[»]
3VUK	X-ray	2.95	F	157-167	[»]
3VUL	X-ray	2.81	F	157-167	[»]
3VUM	X-ray	2.69	F	157-167	[»]
4H39	X-ray	1.99	B	158-167	[»]

ProteinModelPortal

Q9UQF2.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9UQF2. 9 interactions.

MINT

MINT-111691.

STRING

9606.ENSP00000241014.

PTM databases

PhosphoSite

Q9UQF2.

Polymorphism databases

DMDM

17433093.

Proteomic databases

PaxDb

Q9UQF2.

PRIDE

Q9UQF2.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000241014; ENSP00000241014; ENSG00000121653.

GeneID

9479.

KEGG

hsa:9479.

UCSC

uc001nbr.3. human.

Organism-specific databases

CTD

9479.

GeneCards

GC11P045908.

HGNC

HGNC:6882. MAPK8IP1.

HPA

CAB013289.

MIM

125853. phenotype.
604641. gene.

neXtProt

NX_Q9UQF2.

PharmGKB

PA30626.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG266073.

HOGENOM

HOG000231470.

HOVERGEN

HBG018568.

InParanoid

Q9UQF2.

KO

K04434.

OMA

SPCRRSA.

OrthoDB

EOG4BP1BD.

PhylomeDB

Q9UQF2.

Gene expression databases

ArrayExpress

Q9UQF2.

Bgee

Q9UQF2.

CleanEx

HS_MAPK8IP1.

Genevestigator

Q9UQF2.

GermOnline

ENSG00000121653. Homo sapiens.

Family and domain databases

Gene3D

2.30.29.30. 1 hit.

InterPro

IPR011993. PH_like_dom.
IPR006020. PTyr_interaction_dom.
IPR001452. SH3_domain.
[Graphical view]

Pfam

PF00640. PID. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]

SMART

SM00462. PTB. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]

SUPFAM

SSF50044. SH3. 1 hit.

PROSITE

PS01179. PID. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

MAPK8IP1. human.

EvolutionaryTrace

Q9UQF2.

GenomeRNAi

9479.

NextBio

35528.

SOURCE

Search...

Entry information

Entry name

JIP1_HUMAN

Accession

Primary (citable) accession number: Q9UQF2
Secondary accession number(s): D3DQP4, O43407

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 5, 2001
Last sequence update:	May 1, 2000
Last modified:	May 1, 2013
This is version 129 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.