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Protein

Midkine

Gene

MDK

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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).By similarity

GO - Molecular functioni

  1. growth factor activity Source: UniProtKB
  2. heparin binding Source: UniProtKB

GO - Biological processi

  1. adrenal gland development Source: UniProtKB
  2. behavioral fear response Source: Ensembl
  3. cell differentiation Source: UniProtKB
  4. cell migration Source: Ensembl
  5. cerebellar granular layer development Source: Ensembl
  6. cerebral cortex development Source: Ensembl
  7. defecation Source: Ensembl
  8. dentate gyrus development Source: Ensembl
  9. negative regulation of neuron apoptotic process Source: Ensembl
  10. nervous system development Source: UniProtKB
  11. Notch signaling pathway Source: Reactome
  12. positive regulation of cell division Source: UniProtKB-KW
  13. positive regulation of transcription, DNA-templated Source: Ensembl
  14. regulation of behavior Source: Ensembl
  15. response to drug Source: Ensembl
  16. response to glucocorticoid Source: Ensembl
  17. response to wounding Source: UniProtKB
  18. short-term memory Source: Ensembl
  19. signal transduction Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Growth factor, Mitogen

Keywords - Biological processi

Differentiation

Keywords - Ligandi

Heparin-binding

Enzyme and pathway databases

ReactomeiREACT_160205. NOTCH2 Activation and Transmission of Signal to the Nucleus.
SignaLinkiP21741.

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:MDK
Synonyms:MK1, NEGF2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 11

Organism-specific databases

HGNCiHGNC:6972. MDK.

Subcellular locationi

GO - Cellular componenti

  1. cell projection Source: Ensembl
  2. cytoplasm Source: Ensembl
  3. extracellular region Source: Reactome
Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA30717.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 20203 PublicationsAdd
BLAST
Chaini21 – 143123MidkinePRO_0000024662Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi37 ↔ 61
Disulfide bondi45 ↔ 70
Disulfide bondi52 ↔ 74
Disulfide bondi84 ↔ 116
Disulfide bondi94 ↔ 126

Keywords - PTMi

Disulfide bond

Proteomic databases

MaxQBiP21741.
PaxDbiP21741.
PRIDEiP21741.

PTM databases

PhosphoSiteiP21741.

Expressioni

Tissue specificityi

Expressed in various tumor cell lines. In insulinoma tissue predominantly expressed in precancerous lesions.1 Publication

Inductioni

By heparin and retinoic acid.2 Publications

Gene expression databases

BgeeiP21741.
CleanExiHS_MDK.
ExpressionAtlasiP21741. baseline.
GenevestigatoriP21741.

Organism-specific databases

HPAiCAB010055.

Interactioni

Subunit structurei

Homodimer. Interacts with ALK.1 Publication

Protein-protein interaction databases

BioGridi110357. 13 interactions.
DIPiDIP-5789N.
IntActiP21741. 4 interactions.
MINTiMINT-1385688.
STRINGi9606.ENSP00000352852.

Structurei

Secondary structure

1
143
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi29 – 313Combined sources
Beta strandi38 – 436Combined sources
Beta strandi48 – 547Combined sources
Beta strandi57 – 637Combined sources
Beta strandi66 – 683Combined sources
Beta strandi76 – 794Combined sources
Beta strandi96 – 1005Combined sources
Beta strandi111 – 1155Combined sources
Beta strandi118 – 1203Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1MKCNMR-A84-126[»]
1MKNNMR-A23-81[»]
ProteinModelPortaliP21741.
SMRiP21741. Positions 31-127.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP21741.

Family & Domainsi

Sequence similaritiesi

Belongs to the pleiotrophin family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiNOG39111.
GeneTreeiENSGT00390000007640.
HOGENOMiHOG000231473.
HOVERGENiHBG008317.
InParanoidiP21741.
KOiK06828.
OrthoDBiEOG7B05G6.
PhylomeDBiP21741.
TreeFamiTF332376.

Family and domain databases

Gene3Di2.20.60.10. 1 hit.
2.30.90.10. 1 hit.
InterProiIPR000762. 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]
PANTHERiPTHR13850. PTHR13850. 1 hit.
PfamiPF01091. PTN_MK_C. 1 hit.
PF05196. PTN_MK_N. 1 hit.
[Graphical view]
PRINTSiPR00269. PTNMIDKINE.
ProDomiPD005592. PTN_MK_hepar_bd. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SMARTiSM00193. PTN. 1 hit.
[Graphical view]
SUPFAMiSSF57288. SSF57288. 2 hits.
PROSITEiPS00619. PTN_MK_1. 1 hit.
PS00620. PTN_MK_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: P21741-1) [UniParc]FASTAAdd to Basket

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.

« Hide

        10         20         30         40         50
MQHRGFLLLT LLALLALTSA VAKKKDKVKK GGPGSECAEW AWGPCTPSSK
60 70 80 90 100
DCGVGFREGT CGAQTQRIRC RVPCNWKKEF GADCKYKFEN WGACDGGTGT
110 120 130 140
KVRQGTLKKA RYNAQCQETI RVTKPCTPKT KAKAKAKKGK GKD
Length:143
Mass (Da):15,585
Last modified:May 1, 1991 - v1
Checksum:i414A627FF39953C3
GO
Isoform 2 (identifier: P21741-2) [UniParc]FASTAAdd to Basket

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.

Show »
Length:87
Mass (Da):9,512
Checksum:i555280233CBB0AC6
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti21 – 222Missing in 35% of the chains.
VAR_006353

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei26 – 8156Missing in isoform 2. 1 PublicationVSP_047452Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS59226.1. [P21741-2]
CCDS7919.1. [P21741-1]
PIRiJH0385.
RefSeqiNP_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]
UniGeneiHs.82045.

Genome annotation databases

EnsembliENST00000359803; 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]
GeneIDi4192.
KEGGihsa:4192.
UCSCiuc001nco.4. human. [P21741-1]

Polymorphism databases

DMDMi127116.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS59226.1. [P21741-2]
CCDS7919.1. [P21741-1]
PIRiJH0385.
RefSeqiNP_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]
UniGeneiHs.82045.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1MKCNMR-A84-126[»]
1MKNNMR-A23-81[»]
ProteinModelPortaliP21741.
SMRiP21741. Positions 31-127.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110357. 13 interactions.
DIPiDIP-5789N.
IntActiP21741. 4 interactions.
MINTiMINT-1385688.
STRINGi9606.ENSP00000352852.

Chemistry

BindingDBiP21741.
ChEMBLiCHEMBL1949490.

PTM databases

PhosphoSiteiP21741.

Polymorphism databases

DMDMi127116.

Proteomic databases

MaxQBiP21741.
PaxDbiP21741.
PRIDEiP21741.

Protocols and materials databases

DNASUi4192.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000359803; 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]
GeneIDi4192.
KEGGihsa:4192.
UCSCiuc001nco.4. human. [P21741-1]

Organism-specific databases

CTDi4192.
GeneCardsiGC11P046402.
HGNCiHGNC:6972. MDK.
HPAiCAB010055.
MIMi162096. gene.
neXtProtiNX_P21741.
PharmGKBiPA30717.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG39111.
GeneTreeiENSGT00390000007640.
HOGENOMiHOG000231473.
HOVERGENiHBG008317.
InParanoidiP21741.
KOiK06828.
OrthoDBiEOG7B05G6.
PhylomeDBiP21741.
TreeFamiTF332376.

Enzyme and pathway databases

ReactomeiREACT_160205. NOTCH2 Activation and Transmission of Signal to the Nucleus.
SignaLinkiP21741.

Miscellaneous databases

ChiTaRSiMDK. human.
EvolutionaryTraceiP21741.
GeneWikiiMidkine.
GenomeRNAii4192.
NextBioi16518.
PROiP21741.
SOURCEiSearch...

Gene expression databases

BgeeiP21741.
CleanExiHS_MDK.
ExpressionAtlasiP21741. baseline.
GenevestigatoriP21741.

Family and domain databases

Gene3Di2.20.60.10. 1 hit.
2.30.90.10. 1 hit.
InterProiIPR000762. 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]
PANTHERiPTHR13850. PTHR13850. 1 hit.
PfamiPF01091. PTN_MK_C. 1 hit.
PF05196. PTN_MK_N. 1 hit.
[Graphical view]
PRINTSiPR00269. PTNMIDKINE.
ProDomiPD005592. PTN_MK_hepar_bd. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SMARTiSM00193. PTN. 1 hit.
[Graphical view]
SUPFAMiSSF57288. SSF57288. 2 hits.
PROSITEiPS00619. PTN_MK_1. 1 hit.
PS00620. PTN_MK_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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. 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.

Entry informationi

Entry nameiMK_HUMAN
AccessioniPrimary (citable) accession number: P21741
Secondary accession number(s): Q2LEK4, Q9UCC7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: May 1, 1991
Last modified: January 7, 2015
This is version 143 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  5. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.