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P21741 (MK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 138. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Midkine

Short name=MK
Alternative name(s):
Amphiregulin-associated protein
Short name=ARAP
Midgestation and kidney protein
Neurite outgrowth-promoting factor 2
Neurite outgrowth-promoting protein
Gene names
Name:MDK
Synonyms:MK1, NEGF2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length143 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Developmentally regulated, secreted growth factor homologous to pleiotrophin (PTN), which has heparin binding activity. Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation. Involved in neointima formation after arterial injury, possibly by mediating leukocyte recruitment. Also involved in early fetal adrenal gland development By similarity. Ref.2 Ref.11

Subunit structure

Homodimer. Interacts with ALK. Ref.11 Ref.12

Subcellular location

Secreted.

Tissue specificity

Expressed in various tumor cell lines. In insulinoma tissue predominantly expressed in precancerous lesions. Ref.5

Induction

By heparin and retinoic acid. Ref.2 Ref.9

Sequence similarities

Belongs to the pleiotrophin family.

Ontologies

Keywords
   Biological processDifferentiation
   Cellular componentSecreted
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainSignal
   LigandHeparin-binding
   Molecular functionDevelopmental protein
Growth factor
Mitogen
   PTMDisulfide bond
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processNotch signaling pathway

Traceable author statement. Source: Reactome

adrenal gland development

Inferred from sequence or structural similarity. Source: UniProtKB

behavioral fear response

Inferred from electronic annotation. Source: Ensembl

cell differentiation

Non-traceable author statement Ref.3. Source: UniProtKB

cell migration

Inferred from electronic annotation. Source: Ensembl

cerebellar granular layer development

Inferred from electronic annotation. Source: Ensembl

cerebral cortex development

Inferred from electronic annotation. Source: Ensembl

defecation

Inferred from electronic annotation. Source: Ensembl

dentate gyrus development

Inferred from electronic annotation. Source: Ensembl

negative regulation of neuron apoptotic process

Inferred from electronic annotation. Source: Ensembl

nervous system development

Non-traceable author statement Ref.12. Source: UniProtKB

positive regulation of cell division

Inferred from electronic annotation. Source: UniProtKB-KW

positive regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: Ensembl

regulation of behavior

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

response to glucocorticoid

Inferred from electronic annotation. Source: Ensembl

response to wounding

Inferred from sequence or structural similarity. Source: UniProtKB

short-term memory

Inferred from electronic annotation. Source: Ensembl

signal transduction

Non-traceable author statement PubMed 7835084. Source: ProtInc

   Cellular_componentextracellular region

Traceable author statement. Source: Reactome

   Molecular_functiongrowth factor activity

Non-traceable author statement Ref.3. Source: UniProtKB

heparin binding

Inferred from direct assay Ref.12. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P21741-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P21741-2)

Also known as: tMKA;

The sequence of this isoform differs from the canonical sequence as follows:
     26-81: Missing.
Note: Found in cancer tissues with expression in the tumor bodies and surrounding normal cells.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2020 Ref.8 Ref.9 Ref.10
Chain21 – 143123Midkine
PRO_0000024662

Amino acid modifications

Disulfide bond37 ↔ 61
Disulfide bond45 ↔ 70
Disulfide bond52 ↔ 74
Disulfide bond84 ↔ 116
Disulfide bond94 ↔ 126

Natural variations

Alternative sequence26 – 8156Missing in isoform 2.
VSP_047452
Natural variant21 – 222Missing in 35% of the chains.
VAR_006353

Secondary structure

................... 143
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified May 1, 1991. Version 1.
Checksum: 414A627FF39953C3

FASTA14315,585
        10         20         30         40         50         60 
MQHRGFLLLT LLALLALTSA VAKKKDKVKK GGPGSECAEW AWGPCTPSSK DCGVGFREGT 

        70         80         90        100        110        120 
CGAQTQRIRC RVPCNWKKEF GADCKYKFEN WGACDGGTGT KVRQGTLKKA RYNAQCQETI 

       130        140 
RVTKPCTPKT KAKAKAKKGK GKD 

« Hide

Isoform 2 (tMKA) [UniParc].

Checksum: 555280233CBB0AC6
Show »

FASTA879,512

References

« Hide 'large scale' references
[1]"A new family of heparin-binding factors: strong conservation of midkine (MK) sequences between the human and the mouse."
Tsutsui J., Uehara K., Kadomatsu K., Matsubara S., Muramatsu T.
Biochem. Biophys. Res. Commun. 176:792-797(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Kidney.
[2]"Cloning, characterization and developmental regulation of two members of a novel human gene family of neurite outgrowth-promoting proteins."
Kretschmer P.J., Fairhurst J.L., Decker M.M., Chan C.P., Gluzman Y., Boehlen P., Kovesdi I.
Growth Factors 5:99-114(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INDUCTION.
Tissue: Fetal brain.
[3]"Genomic structure of human midkine (MK), a retinoic acid-responsive growth/differentiation factor."
Uehara K., Matsubara S., Kadomatsu K., Tsutsui J., Muramatsu T.
J. Biochem. 111:563-567(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"Structure of the gene coding for the human retinoic acid-inducible factor, MK."
Fairhurst J.L., Kretschmer P.J., Gluzman Y., Boehlen P., Kovesdi I.
DNA Cell Biol. 12:139-147(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Fetal brain.
[5]"Abnormal expression, highly efficient detection and novel truncations of midkine in human tumors, cancers and cell lines."
Tao P., Xu D., Lin S., Ouyang G.L., Chang Y., Chen Q., Yuan Y., Zhuo X., Luo Q., Li J., Li B., Ruan L., Li Q., Li Z.
Cancer Lett. 253:60-67(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY.
[6]"Human chromosome 11 DNA sequence and analysis including novel gene identification."
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. expand/collapse author list , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y.
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Uterus.
[8]"Amphiregulin-associated protein: complete amino acid sequence of a protein produced by the 12-0-tetradecanoylphorbol-13-acetate-treated human breast adenocarcinoma cell line MCF-7."
Shoyab M., McDonald V.L., Dick K., Modrell B., Malik N., Plowman G.D.
Biochem. Biophys. Res. Commun. 179:572-578(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 21-143.
[9]"Identification of novel heparin-releasable proteins, as well as the cytokines midkine and pleiotrophin, in human postheparin plasma."
Novotny W.F., Maffi T., Mehta R.L., Milner P.G.
Arterioscler. Thromb. 13:1798-1805(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 21-35, INDUCTION.
Tissue: Plasma.
[10]"Signal peptide prediction based on analysis of experimentally verified cleavage sites."
Zhang Z., Henzel W.J.
Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 21-35.
[11]"Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types."
Stoica G.E., Kuo A., Powers C., Bowden E.T., Sale E.B., Riegel A.T., Wellstein A.
J. Biol. Chem. 277:35990-35998(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ALK, FUNCTION.
[12]"Solution structure of midkine, a new heparin-binding growth factor."
Iwasaki W., Nagata K., Hatanaka H., Inui T., Kimura T., Muramatsu T., Yoshida K., Tasumi M., Inagaki F.
EMBO J. 16:6936-6946(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 23-81 AND 84-126, HOMODIMERIZATION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M69148 mRNA. Translation: AAA58478.1.
X55110 mRNA. Translation: CAA38908.1.
D10604 Genomic DNA. Translation: BAA01457.1.
M94250 Genomic DNA. Translation: AAA59850.1.
DQ323888 mRNA. Translation: ABC55425.1.
AC116021 Genomic DNA. No translation available.
BC011704 mRNA. Translation: AAH11704.1.
CCDSCCDS59226.1. [P21741-2]
CCDS7919.1. [P21741-1]
PIRJH0385.
RefSeqNP_001012333.1. NM_001012333.2. [P21741-1]
NP_001012334.1. NM_001012334.2. [P21741-1]
NP_001257479.1. NM_001270550.1. [P21741-1]
NP_001257480.1. NM_001270551.1. [P21741-1]
NP_001257481.1. NM_001270552.1. [P21741-2]
NP_002382.1. NM_002391.4. [P21741-1]
UniGeneHs.82045.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1MKCNMR-A84-126[»]
1MKNNMR-A23-81[»]
ProteinModelPortalP21741.
SMRP21741. Positions 31-127.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110357. 13 interactions.
DIPDIP-5789N.
IntActP21741. 4 interactions.
MINTMINT-1385688.
STRING9606.ENSP00000352852.

Chemistry

BindingDBP21741.
ChEMBLCHEMBL1949490.

PTM databases

PhosphoSiteP21741.

Polymorphism databases

DMDM127116.

Proteomic databases

MaxQBP21741.
PaxDbP21741.
PRIDEP21741.

Protocols and materials databases

DNASU4192.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000359803; ENSP00000352852; ENSG00000110492. [P21741-1]
ENST00000395565; ENSP00000378932; ENSG00000110492. [P21741-1]
ENST00000395566; ENSP00000378933; ENSG00000110492. [P21741-1]
ENST00000395569; ENSP00000378936; ENSG00000110492. [P21741-2]
ENST00000405308; ENSP00000385451; ENSG00000110492. [P21741-1]
ENST00000407067; ENSP00000384034; ENSG00000110492. [P21741-1]
GeneID4192.
KEGGhsa:4192.
UCSCuc001nco.4. human. [P21741-1]

Organism-specific databases

CTD4192.
GeneCardsGC11P046402.
HGNCHGNC:6972. MDK.
HPACAB010055.
MIM162096. gene.
neXtProtNX_P21741.
PharmGKBPA30717.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG39111.
HOGENOMHOG000231473.
HOVERGENHBG008317.
KOK06828.
OrthoDBEOG7B05G6.
PhylomeDBP21741.
TreeFamTF332376.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
SignaLinkP21741.

Gene expression databases

BgeeP21741.
CleanExHS_MDK.
GenevestigatorP21741.

Family and domain databases

Gene3D2.20.60.10. 1 hit.
2.30.90.10. 1 hit.
InterProIPR000762. Midkine_heparin-bd_GF.
IPR020090. PTN/MK_C_dom.
IPR020091. PTN/MK_diS.
IPR020089. PTN/MK_N_dom.
IPR020092. PTN_MK_heparin-bd_GF_CS.
[Graphical view]
PANTHERPTHR13850. PTHR13850. 1 hit.
PfamPF01091. PTN_MK_C. 1 hit.
PF05196. PTN_MK_N. 1 hit.
[Graphical view]
PRINTSPR00269. PTNMIDKINE.
ProDomPD005592. PTN_MK_hepar_bd. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SMARTSM00193. PTN. 1 hit.
[Graphical view]
SUPFAMSSF57288. SSF57288. 2 hits.
PROSITEPS00619. PTN_MK_1. 1 hit.
PS00620. PTN_MK_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMDK. human.
EvolutionaryTraceP21741.
GeneWikiMidkine.
GenomeRNAi4192.
NextBio16518.
PROP21741.
SOURCESearch...

Entry information

Entry nameMK_HUMAN
AccessionPrimary (citable) accession number: P21741
Secondary accession number(s): Q2LEK4, Q9UCC7
Entry history
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: May 1, 1991
Last modified: July 9, 2014
This is version 138 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM