Reviewed, UniProtKB/Swiss-Prot Q9UQF2 (JIP1_HUMAN)

Names and origin

Protein names

Recommended name:
    C-jun-amino-terminal kinase-interacting protein 1
      Short name=JNK-interacting protein 1
      Short name=JIP-1
Alternative name(s):
    JNK MAP kinase scaffold protein 1
    Islet-brain 1
      Short name=IB-1
    Mitogen-activated protein kinase 8-interacting protein 1

Gene names

Name:	MAPK8IP1
Synonyms:	IB1, JIP1, PRKM8IP

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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 RGNEF. 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 By similarity. Ref.3 Ref.4 Ref.5 Ref.6
Subcellular location	Cytoplasm By similarity. Cytoplasm › perinuclear region By similarity. Nucleus By similarity. 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.3
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.
Post-translational modification	Phosphorylated by MAPK8, MAPK9 and MAPK10. Phosphorylation on Thr-103 is also necessary for the dissociation and activation of MAP3K12. Ref.7 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.9
Involvement in disease	Defects in MAPK8IP1 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance. Ref.11
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 Nucleus
Coding sequence diversity	Polymorphism
Disease	Diabetes mellitus Disease mutation
Domain	Repeat SH3 domain
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	vesicle-mediated transport Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell perinuclear region of cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	MAP-kinase scaffold activity Ref.4 Inferred from physical interaction. Source: UniProtKB kinesin binding Ref.4 Inferred from physical interaction. Source: UniProtKB protein kinase inhibitor activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APP	P05067	3	EBI-78404,EBI-77613
App	P12023	1	EBI-78404,EBI-78814	From a different organism.
App	P12023-2	1	EBI-78404,EBI-286828	From a different organism.
MAP3K7	O43318	1	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)
	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	103	1	Phosphothreonine; by MAPK8, MAPK9 and MAPK10
	Modified residue	205	1	Phosphothreonine; by MAPK8, MAPK9 and MAPK10
Natural variations
	Natural variant	59	1	S → N in NIDDM. Ref.11		VAR_012243
	Natural variant	322	1	A → V: dbSNP rs34420676.		VAR_049664
	Natural variant	353	1	R → Q: dbSNP rs12295161.		VAR_049665
Experimental info
	Mutagenesis	160	1	R → G: Abolishes MAPK9 interaction.
	Mutagenesis	161	1	P → G: Abolishes MAPK9 interaction.
	Mutagenesis	704	1	P → A: No effect on KNS2 binding.
	Mutagenesis	709	1	Y → A: Abolishes KNS2 binding.

Sequences

	Sequence		Length	Mass (Da)
	Q9UQF2-1 [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: 9933567] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Insulinoma.
[2]	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.
[3]	"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: 10574993] [Abstract] Cited for: INTERACTION WITH RGNEF, SUBCELLULAR LOCATION.
[4]	"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: 11238452] [Abstract] Cited for: MUTAGENESIS, INTERACTION WITH KINESIN.
[5]	"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: 11726277] [Abstract] Cited for: INTERACTION WITH MAP3K13.
[6]	"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: 11912189] [Abstract] Cited for: INTERACTION WITH APP.
[7]	"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: 12756254] [Abstract] Cited for: PHOSPHORYLATION BY JNK, MUTAGENESIS.
[8]	"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: 11147798] [Abstract] Cited for: PEPTIDE INHIBITORS OF JNK.
[9]	"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: 14507925] [Abstract] Cited for: CALCIUM- AND PROTEASOME-DEPENDENT DEGRADATION.
[10]	"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: 12937412] [Abstract] Cited for: PROTECTION AGAINST EXCITOTOXICITY AND CEREBRAL ISCHEMIA.
[11]	"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: 10700186] [Abstract] Cited for: VARIANT NIDDM ASN-59.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF074091 mRNA. Translation: AAD20443.1.
AF007134 mRNA. Translation: AAC19150.1.

IPI

IPI00023133.

RefSeq

NP_005447.1.

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	[»]

SMR

Q9UQF2. Positions 490-549, 565-700.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9UQF2. 17 interactions.

STRING

Q9UQF2.

PTM databases

PhosphoSite

Q9UQF2.

Proteomic databases

PRIDE

Q9UQF2.

Genome annotation databases

Ensembl

ENST00000241014; ENSP00000241014; ENSG00000121653; Homo sapiens. [Genome view]

GeneID

9479.

KEGG

hsa:9479.

UCSC

uc001nbr.1. human.

Organism-specific databases

CTD

9479.

GeneCards

GC11P045863.

H-InvDB

HIX0035850.
HIX0059692.

HGNC

HGNC:6882. MAPK8IP1.

HPA

CAB013289.

MIM

125853. phenotype.
604641. gene.

PharmGKB

PA30626.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG08481.

HOGENOM

HBG717444.

HOVERGEN

Q9UQF2.

InParanoid

Q9UQF2.

OMA

GRGHSHR.

OrthoDB

EOG9GQSQT.

PhylomeDB

Q9UQF2.

Gene expression databases

ArrayExpress

Q9UQF2.

Bgee

Q9UQF2.

CleanEx

HS_MAPK8IP1.

Genevestigator

Q9UQF2.

GermOnline

ENSG00000121653. Homo sapiens.

Family and domain databases

InterPro

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

Gene3D

G3DSA:2.30.29.30. PH_type. 1 hit.

Pfam

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

SMART

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

PROSITE

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

ProtoNet

Search...

Other Resources

NextBio

35528.

SOURCE

Search...

Entry information

Entry name

JIP1_HUMAN

Accession

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

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 5, 2001
Last sequence update:	May 1, 2000
Last modified:	January 19, 2010
This is version 96 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.