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P21741

- MK_HUMAN

UniProt

P21741 - MK_HUMAN

Protein

Midkine

Gene

MDK

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
  1. 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

    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. extracellular region Source: Reactome

    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.
    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 – 313
    Beta strandi38 – 436
    Beta strandi48 – 547
    Beta strandi57 – 637
    Beta strandi66 – 683
    Beta strandi76 – 794
    Beta strandi96 – 1005
    Beta strandi111 – 1155
    Beta strandi118 – 1203

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    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.
    HOGENOMiHOG000231473.
    HOVERGENiHBG008317.
    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

    MQHRGFLLLT LLALLALTSA VAKKKDKVKK GGPGSECAEW AWGPCTPSSK    50
    DCGVGFREGT CGAQTQRIRC RVPCNWKKEF GADCKYKFEN WGACDGGTGT 100
    KVRQGTLKKA RYNAQCQETI RVTKPCTPKT KAKAKAKKGK GKD 143
    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:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    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 .
    CCDSi CCDS59226.1. [P21741-2 ]
    CCDS7919.1. [P21741-1 ]
    PIRi JH0385.
    RefSeqi NP_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 ]
    UniGenei Hs.82045.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1MKC NMR - A 84-126 [» ]
    1MKN NMR - A 23-81 [» ]
    ProteinModelPortali P21741.
    SMRi P21741. Positions 31-127.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 110357. 13 interactions.
    DIPi DIP-5789N.
    IntActi P21741. 4 interactions.
    MINTi MINT-1385688.
    STRINGi 9606.ENSP00000352852.

    Chemistry

    BindingDBi P21741.
    ChEMBLi CHEMBL1949490.

    PTM databases

    PhosphoSitei P21741.

    Polymorphism databases

    DMDMi 127116.

    Proteomic databases

    MaxQBi P21741.
    PaxDbi P21741.
    PRIDEi P21741.

    Protocols and materials databases

    DNASUi 4192.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000359803 ; 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 ]
    GeneIDi 4192.
    KEGGi hsa:4192.
    UCSCi uc001nco.4. human. [P21741-1 ]

    Organism-specific databases

    CTDi 4192.
    GeneCardsi GC11P046402.
    HGNCi HGNC:6972. MDK.
    HPAi CAB010055.
    MIMi 162096. gene.
    neXtProti NX_P21741.
    PharmGKBi PA30717.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG39111.
    HOGENOMi HOG000231473.
    HOVERGENi HBG008317.
    KOi K06828.
    OrthoDBi EOG7B05G6.
    PhylomeDBi P21741.
    TreeFami TF332376.

    Enzyme and pathway databases

    Reactomei REACT_160205. NOTCH2 Activation and Transmission of Signal to the Nucleus.
    SignaLinki P21741.

    Miscellaneous databases

    ChiTaRSi MDK. human.
    EvolutionaryTracei P21741.
    GeneWikii Midkine.
    GenomeRNAii 4192.
    NextBioi 16518.
    PROi P21741.
    SOURCEi Search...

    Gene expression databases

    Bgeei P21741.
    CleanExi HS_MDK.
    Genevestigatori P21741.

    Family and domain databases

    Gene3Di 2.20.60.10. 1 hit.
    2.30.90.10. 1 hit.
    InterProi IPR000762. 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 ]
    PANTHERi PTHR13850. PTHR13850. 1 hit.
    Pfami PF01091. PTN_MK_C. 1 hit.
    PF05196. PTN_MK_N. 1 hit.
    [Graphical view ]
    PRINTSi PR00269. PTNMIDKINE.
    ProDomi PD005592. PTN_MK_hepar_bd. 1 hit.
    [Graphical view ] [Entries sharing at least one domain ]
    SMARTi SM00193. PTN. 1 hit.
    [Graphical view ]
    SUPFAMi SSF57288. SSF57288. 2 hits.
    PROSITEi PS00619. PTN_MK_1. 1 hit.
    PS00620. PTN_MK_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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: October 1, 2014
    This is version 140 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