MK_HUMAN
ID MK_HUMAN Reviewed; 143 AA.
AC P21741; Q2LEK4; Q9UCC7;
DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1991, sequence version 1.
DT 03-AUG-2022, entry version 194.
DE RecName: Full=Midkine {ECO:0000303|PubMed:2025291};
DE Short=MK {ECO:0000303|PubMed:2025291};
DE AltName: Full=Amphiregulin-associated protein {ECO:0000303|PubMed:1883381};
DE Short=ARAP {ECO:0000303|PubMed:1883381};
DE AltName: Full=Midgestation and kidney protein;
DE AltName: Full=Neurite outgrowth-promoting factor 2;
DE AltName: Full=Neurite outgrowth-promoting protein {ECO:0000303|PubMed:1768439};
DE Flags: Precursor;
GN Name=MDK {ECO:0000312|HGNC:HGNC:6972}; Synonyms=MK1, NEGF2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RX PubMed=2025291; DOI=10.1016/s0006-291x(05)80255-4;
RA Tsutsui J., Uehara K., Kadomatsu K., Matsubara S., Muramatsu T.;
RT "A new family of heparin-binding factors: strong conservation of midkine
RT (MK) sequences between the human and the mouse.";
RL Biochem. Biophys. Res. Commun. 176:792-797(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND INDUCTION.
RC TISSUE=Fetal brain;
RX PubMed=1768439; DOI=10.3109/08977199109000275;
RA Kretschmer P.J., Fairhurst J.L., Decker M.M., Chan C.P., Gluzman Y.,
RA Boehlen P., Kovesdi I.;
RT "Cloning, characterization and developmental regulation of two members of a
RT novel human gene family of neurite outgrowth-promoting proteins.";
RL Growth Factors 5:99-114(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1639750; DOI=10.1093/oxfordjournals.jbchem.a123797;
RA Uehara K., Matsubara S., Kadomatsu K., Tsutsui J., Muramatsu T.;
RT "Genomic structure of human midkine (MK), a retinoic acid-responsive
RT growth/differentiation factor.";
RL J. Biochem. 111:563-567(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Fetal brain;
RX PubMed=8471163; DOI=10.1089/dna.1993.12.139;
RA Fairhurst J.L., Kretschmer P.J., Gluzman Y., Boehlen P., Kovesdi I.;
RT "Structure of the gene coding for the human retinoic acid-inducible factor,
RT MK.";
RL DNA Cell Biol. 12:139-147(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=17379400; DOI=10.1016/j.canlet.2007.01.019;
RA Tao P., Xu D., Lin S., Ouyang G.L., Chang Y., Chen Q., Yuan Y., Zhuo X.,
RA Luo Q., Li J., Li B., Ruan L., Li Q., Li Z.;
RT "Abnormal expression, highly efficient detection and novel truncations of
RT midkine in human tumors, cancers and cell lines.";
RL Cancer Lett. 253:60-67(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 21-143.
RX PubMed=1883381; DOI=10.1016/0006-291x(91)91409-6;
RA Shoyab M., McDonald V.L., Dick K., Modrell B., Malik N., Plowman G.D.;
RT "Amphiregulin-associated protein: complete amino acid sequence of a protein
RT produced by the 12-0-tetradecanoylphorbol-13-acetate-treated human breast
RT adenocarcinoma cell line MCF-7.";
RL Biochem. Biophys. Res. Commun. 179:572-578(1991).
RN [9]
RP PROTEIN SEQUENCE OF 21-35, AND INDUCTION.
RC TISSUE=Plasma;
RX PubMed=8241100; DOI=10.1161/01.atv.13.12.1798;
RA Novotny W.F., Maffi T., Mehta R.L., Milner P.G.;
RT "Identification of novel heparin-releasable proteins, as well as the
RT cytokines midkine and pleiotrophin, in human postheparin plasma.";
RL Arterioscler. Thromb. 13:1798-1805(1993).
RN [10]
RP PROTEIN SEQUENCE OF 21-35.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [11]
RP INTERACTION WITH PTPRZ1, AND FUNCTION.
RX PubMed=10212223; DOI=10.1074/jbc.274.18.12474;
RA Maeda N., Ichihara-Tanaka K., Kimura T., Kadomatsu K., Muramatsu T.,
RA Noda M.;
RT "A receptor-like protein-tyrosine phosphatase PTPzeta/RPTPbeta binds a
RT heparin-binding growth factor midkine. Involvement of arginine 78 of
RT midkine in the high affinity binding to PTPzeta.";
RL J. Biol. Chem. 274:12474-12479(1999).
RN [12]
RP INTERACTION WITH LRP1; NCAM1 AND LRP2, AND FUNCTION.
RX PubMed=10772929; DOI=10.1006/bbrc.2000.2549;
RA Muramatsu H., Zou K., Sakaguchi N., Ikematsu S., Sakuma S., Muramatsu T.;
RT "LDL receptor-related protein as a component of the midkine receptor.";
RL Biochem. Biophys. Res. Commun. 270:936-941(2000).
RN [13]
RP FUNCTION.
RX PubMed=10683378; DOI=10.1172/jci7208;
RA Horiba M., Kadomatsu K., Nakamura E., Muramatsu H., Ikematsu S., Sakuma S.,
RA Hayashi K., Yuzawa Y., Matsuo S., Kuzuya M., Kaname T., Hirai M., Saito H.,
RA Muramatsu T.;
RT "Neointima formation in a restenosis model is suppressed in midkine-
RT deficient mice.";
RL J. Clin. Invest. 105:489-495(2000).
RN [14]
RP INTERACTION WITH GPC2 AND SCD3, AND FUNCTION.
RX PubMed=12084985; DOI=10.1023/a:1016042303253;
RA Kurosawa N., Chen G.Y., Kadomatsu K., Ikematsu S., Sakuma S., Muramatsu T.;
RT "Glypican-2 binds to midkine: the role of glypican-2 in neuronal cell
RT adhesion and neurite outgrowth.";
RL Glycoconj. J. 18:499-507(2001).
RN [15]
RP INTERACTION WITH ALK, AND FUNCTION.
RX PubMed=12122009; DOI=10.1074/jbc.m205749200;
RA Stoica G.E., Kuo A., Powers C., Bowden E.T., Sale E.B., Riegel A.T.,
RA Wellstein A.;
RT "Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth
RT factor for different cell types.";
RL J. Biol. Chem. 277:35990-35998(2002).
RN [16]
RP INTERACTION WITH NCL.
RX PubMed=12147681; DOI=10.1074/jbc.m201194200;
RA Said E.A., Krust B., Nisole S., Svab J., Briand J.P., Hovanessian A.G.;
RT "The anti-HIV cytokine midkine binds the cell surface-expressed nucleolin
RT as a low affinity receptor.";
RL J. Biol. Chem. 277:37492-37502(2002).
RN [17]
RP INTERACTION WITH LRP6 AND LRP8, AND FUNCTION.
RX PubMed=12573468; DOI=10.1016/s0168-0102(02)00226-2;
RA Sakaguchi N., Muramatsu H., Ichihara-Tanaka K., Maeda N., Noda M.,
RA Yamamoto T., Michikawa M., Ikematsu S., Sakuma S., Muramatsu T.;
RT "Receptor-type protein tyrosine phosphatase zeta as a component of the
RT signaling receptor complex for midkine-dependent survival of embryonic
RT neurons.";
RL Neurosci. Res. 45:219-224(2003).
RN [18]
RP INTERACTION WITH ITGB1; ITGA4; ITGA6, AND FUNCTION.
RX PubMed=15466886; DOI=10.1242/jcs.01423;
RA Muramatsu H., Zou P., Suzuki H., Oda Y., Chen G.Y., Sakaguchi N.,
RA Sakuma S., Maeda N., Noda M., Takada Y., Muramatsu T.;
RT "alpha4beta1- and alpha6beta1-integrins are functional receptors for
RT midkine, a heparin-binding growth factor.";
RL J. Cell Sci. 117:5405-5415(2004).
RN [19]
RP FUNCTION, AND INTERACTION WITH NOTCH2.
RX PubMed=18469519; DOI=10.4161/cc.7.11.5952;
RA Huang Y., Hoque M.O., Wu F., Trink B., Sidransky D., Ratovitski E.A.;
RT "Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-
RT Stat3 signaling in human keratinocytes.";
RL Cell Cycle 7:1613-1622(2008).
RN [20]
RP FUNCTION.
RX PubMed=22323540; DOI=10.4049/jimmunol.1102346;
RA Sonobe Y., Li H., Jin S., Kishida S., Kadomatsu K., Takeuchi H., Mizuno T.,
RA Suzumura A.;
RT "Midkine inhibits inducible regulatory T cell differentiation by
RT suppressing the development of tolerogenic dendritic cells.";
RL J. Immunol. 188:2602-2611(2012).
RN [21]
RP FUNCTION.
RX PubMed=24458438; DOI=10.1182/blood-2013-06-510875;
RA Weckbach L.T., Gola A., Winkelmann M., Jakob S.M., Groesser L.,
RA Borgolte J., Pogoda F., Pick R., Pruenster M., Mueller-Hoecker J.,
RA Deindl E., Sperandio M., Walzog B.;
RT "The cytokine midkine supports neutrophil trafficking during acute
RT inflammation by promoting adhesion via beta2 integrins (CD11/CD18).";
RL Blood 123:1887-1896(2014).
RN [22]
RP STRUCTURE BY NMR OF 23-81 AND 84-126, AND HOMODIMERIZATION.
RX PubMed=9384573; DOI=10.1093/emboj/16.23.6936;
RA Iwasaki W., Nagata K., Hatanaka H., Inui T., Kimura T., Muramatsu T.,
RA Yoshida K., Tasumi M., Inagaki F.;
RT "Solution structure of midkine, a new heparin-binding growth factor.";
RL EMBO J. 16:6936-6946(1997).
CC -!- FUNCTION: Secreted protein that functions as cytokine and growth factor
CC and mediates its signal through cell-surface proteoglycan and non-
CC proteoglycan receptors (PubMed:18469519, PubMed:12573468,
CC PubMed:12122009, PubMed:10212223, PubMed:24458438, PubMed:15466886,
CC PubMed:12084985, PubMed:10772929). Binds cell-surface proteoglycan
CC receptors via their chondroitin sulfate (CS) groups (PubMed:12084985,
CC PubMed:10212223). Thereby regulates many processes like inflammatory
CC response, cell proliferation, cell adhesion, cell growth, cell
CC survival, tissue regeneration, cell differentiation and cell migration
CC (PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:10683378,
CC PubMed:24458438, PubMed:22323540, PubMed:12084985, PubMed:15466886,
CC PubMed:10772929). Participates in inflammatory processes by exerting
CC two different activities. Firstly, mediates neutrophils and macrophages
CC recruitment to the sites of inflammation both by direct action by
CC cooperating namely with ITGB2 via LRP1 and by inducing chemokine
CC expression (PubMed:10683378, PubMed:24458438). This inflammation can be
CC accompanied by epithelial cell survival and smooth muscle cell
CC migration after renal and vessel damage, respectively
CC (PubMed:10683378). Secondly, suppresses the development of tolerogenic
CC dendric cells thereby inhibiting the differentiation of regulatory T
CC cells and also promote T cell expansion through NFAT signaling and Th1
CC cell differentiation (PubMed:22323540). Promotes tissue regeneration
CC after injury or trauma. After heart damage negatively regulates the
CC recruitment of inflammatory cells and mediates cell survival through
CC activation of anti-apoptotic signaling pathways via MAPKs and AKT
CC pathways through the activation of angiogenesis (By similarity). Also
CC facilitates liver regeneration as well as bone repair by recruiting
CC macrophage at trauma site and by promoting cartilage development by
CC facilitating chondrocyte differentiation (By similarity). Plays a role
CC in brain by promoting neural precursor cells survival and growth
CC through interaction with heparan sulfate proteoglycans (By similarity).
CC Binds PTPRZ1 and promotes neuronal migration and embryonic neurons
CC survival (PubMed:10212223). Binds SDC3 or GPC2 and mediates neurite
CC outgrowth and cell adhesion (PubMed:12084985, PubMed:1768439). Binds
CC chondroitin sulfate E and heparin leading to inhibition of neuronal
CC cell adhesion induced by binding with GPC2 (PubMed:12084985). Binds
CC CSPG5 and promotes elongation of oligodendroglial precursor-like cells
CC (By similarity). Also binds ITGA6:ITGB1 complex; this interaction
CC mediates MDK-induced neurite outgrowth (PubMed:15466886,
CC PubMed:1768439). Binds LRP1; promotes neuronal survival
CC (PubMed:10772929). Binds ITGA4:ITGB1 complex; this interaction mediates
CC MDK-induced osteoblast cells migration through PXN phosphorylation
CC (PubMed:15466886). Binds anaplastic lymphoma kinase (ALK) which induces
CC ALK activation and subsequent phosphorylation of the insulin receptor
CC substrate (IRS1), followed by the activation of mitogen-activated
CC protein kinase (MAPK) and PI3-kinase, and the induction of cell
CC proliferation (PubMed:12122009). Promotes epithelial to mesenchymal
CC transition through interaction with NOTCH2 (PubMed:18469519). During
CC arteriogenesis, plays a role in vascular endothelial cell proliferation
CC by inducing VEGFA expression and release which in turn induces nitric
CC oxide synthase expression. Moreover activates vasodilation through
CC nitric oxide synthase activation (By similarity). Negatively regulates
CC bone formation in response to mechanical load by inhibiting Wnt/beta-
CC catenin signaling in osteoblasts (By similarity). In addition plays a
CC role in hippocampal development, working memory, auditory response,
CC early fetal adrenal gland development and the female reproductive
CC system (By similarity). {ECO:0000250|UniProtKB:P12025,
CC ECO:0000250|UniProtKB:Q9R1S9, ECO:0000269|PubMed:10212223,
CC ECO:0000269|PubMed:10683378, ECO:0000269|PubMed:10772929,
CC ECO:0000269|PubMed:12084985, ECO:0000269|PubMed:12122009,
CC ECO:0000269|PubMed:12573468, ECO:0000269|PubMed:15466886,
CC ECO:0000269|PubMed:1768439, ECO:0000269|PubMed:18469519,
CC ECO:0000269|PubMed:22323540, ECO:0000269|PubMed:24458438}.
CC -!- SUBUNIT: Homodimer. Interacts with ALK (PubMed:12122009). Interacts
CC with LRP1; promotes neuronal survival (PubMed:10772929). Interacts with
CC LRP2 (PubMed:10772929). Interacts with NCAM1 (PubMed:10772929).
CC Interacts (via C-terminal) with PTPRZ1 (via chondroitin sulfate
CC chains); this interaction is inhibited by PTN; this interaction
CC promotes neuronal migration (PubMed:10212223). Interacts with NCL; this
CC interaction promotes NCL clustering and lateral movements of this
CC complex into lipid rafts leading to MDK internalization
CC (PubMed:12147681). Interacts with LRP6 and LRP8: this interaction is
CC calcium dependent (PubMed:12573468). Interacts with ITGA4
CC (PubMed:15466886). Interacts with ITGA6 (PubMed:15466886). Interacts
CC with ITGB1 (PubMed:15466886). Interacts with ITGA4:ITGB1 complex; this
CC interaction mediates MDK-induced osteoblast cells migration through PXN
CC phosphorylation (PubMed:15466886). Interacts with ITGA6:ITGB1 complex;
CC this interaction mediates MDK-induced neurite outgrowth
CC (PubMed:15466886). Interacts with NOTCH2; this interaction mediates a
CC nuclear accumulation of NOTCH2 and therefore activation of NOTCH2
CC signaling leading to interaction between HES1 and STAT3
CC (PubMed:18469519). Interacts with GPC2 (via heparan sulfate chain);
CC this interaction is inhibited by heparin followed by chondroitin
CC sulfate E; this interaction induces GPC2 clustering through heparan
CC sulfate chain; this interaction induces neuronal cell adhesion and
CC neurite outgrowth (PubMed:12084985). Interacts with SDC3; this
CC interaction induces SDC3 clustering; this interaction induces neuronal
CC cell adhesion and neurite outgrowth (PubMed:12084985). Interacts with
CC SDC1 (By similarity). Interacts with CSPG5; this interaction promotes
CC elongation of oligodendroglial precursor-like cells (By similarity).
CC {ECO:0000250|UniProtKB:P12025, ECO:0000269|PubMed:10212223,
CC ECO:0000269|PubMed:10772929, ECO:0000269|PubMed:12084985,
CC ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:12147681,
CC ECO:0000269|PubMed:12573468, ECO:0000269|PubMed:15466886,
CC ECO:0000269|PubMed:18469519}.
CC -!- INTERACTION:
CC P21741; Q9BXS5: AP1M1; NbExp=3; IntAct=EBI-722444, EBI-541426;
CC P21741; P08631-2: HCK; NbExp=3; IntAct=EBI-722444, EBI-9834454;
CC P21741; Q8TAC2: JOSD2; NbExp=3; IntAct=EBI-722444, EBI-12205593;
CC P21741; Q96C03-3: MIEF2; NbExp=3; IntAct=EBI-722444, EBI-11988931;
CC P21741; Q9UMS0: NFU1; NbExp=3; IntAct=EBI-722444, EBI-725252;
CC P21741; Q96AL5: PBX3; NbExp=3; IntAct=EBI-722444, EBI-741171;
CC P21741; Q8N0V3: RBFA; NbExp=3; IntAct=EBI-722444, EBI-3232108;
CC P21741; Q15560: TCEA2; NbExp=3; IntAct=EBI-722444, EBI-710310;
CC P21741; Q6PL24: TMED8; NbExp=3; IntAct=EBI-722444, EBI-11603430;
CC P21741; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-722444, EBI-741480;
CC P21741; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-722444, EBI-947187;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P21741-1; Sequence=Displayed;
CC Name=2; Synonyms=tMKA;
CC IsoId=P21741-2; Sequence=VSP_047452;
CC -!- TISSUE SPECIFICITY: Expressed in various tumor cell lines. In
CC insulinoma tissue predominantly expressed in precancerous lesions.
CC {ECO:0000269|PubMed:17379400}.
CC -!- INDUCTION: By heparin and retinoic acid. {ECO:0000269|PubMed:1768439,
CC ECO:0000269|PubMed:8241100}.
CC -!- MISCELLANEOUS: [Isoform 2]: Found in cancer tissues with expression in
CC the tumor bodies and surrounding normal cells. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the pleiotrophin family. {ECO:0000305}.
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DR EMBL; M69148; AAA58478.1; -; mRNA.
DR EMBL; X55110; CAA38908.1; -; mRNA.
DR EMBL; D10604; BAA01457.1; -; Genomic_DNA.
DR EMBL; M94250; AAA59850.1; -; Genomic_DNA.
DR EMBL; DQ323888; ABC55425.1; -; mRNA.
DR EMBL; AC116021; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC011704; AAH11704.1; -; mRNA.
DR CCDS; CCDS59226.1; -. [P21741-2]
DR CCDS; CCDS7919.1; -. [P21741-1]
DR PIR; JH0385; JH0385.
DR RefSeq; NP_001012333.1; NM_001012333.2. [P21741-1]
DR RefSeq; NP_001012334.1; NM_001012334.2. [P21741-1]
DR RefSeq; NP_001257479.1; NM_001270550.1. [P21741-1]
DR RefSeq; NP_001257480.1; NM_001270551.1. [P21741-1]
DR RefSeq; NP_001257481.1; NM_001270552.1. [P21741-2]
DR RefSeq; NP_002382.1; NM_002391.4. [P21741-1]
DR RefSeq; XP_011518418.1; XM_011520116.2. [P21741-1]
DR RefSeq; XP_016873253.1; XM_017017764.1. [P21741-1]
DR PDB; 1MKC; NMR; -; A=84-126.
DR PDB; 1MKN; NMR; -; A=23-81.
DR PDBsum; 1MKC; -.
DR PDBsum; 1MKN; -.
DR AlphaFoldDB; P21741; -.
DR SMR; P21741; -.
DR BioGRID; 110357; 66.
DR DIP; DIP-5789N; -.
DR IntAct; P21741; 46.
DR MINT; P21741; -.
DR STRING; 9606.ENSP00000385451; -.
DR BindingDB; P21741; -.
DR ChEMBL; CHEMBL1949490; -.
DR iPTMnet; P21741; -.
DR PhosphoSitePlus; P21741; -.
DR BioMuta; MDK; -.
DR DMDM; 127116; -.
DR EPD; P21741; -.
DR jPOST; P21741; -.
DR MassIVE; P21741; -.
DR MaxQB; P21741; -.
DR PaxDb; P21741; -.
DR PeptideAtlas; P21741; -.
DR PRIDE; P21741; -.
DR ProteomicsDB; 53896; -. [P21741-1]
DR ProteomicsDB; 61338; -.
DR ABCD; P21741; 1 sequenced antibody.
DR Antibodypedia; 4105; 590 antibodies from 38 providers.
DR DNASU; 4192; -.
DR Ensembl; ENST00000359803.7; ENSP00000352852.2; ENSG00000110492.17. [P21741-1]
DR Ensembl; ENST00000395565.5; ENSP00000378932.1; ENSG00000110492.17. [P21741-1]
DR Ensembl; ENST00000395566.9; ENSP00000378933.4; ENSG00000110492.17. [P21741-1]
DR Ensembl; ENST00000395569.8; ENSP00000378936.4; ENSG00000110492.17. [P21741-2]
DR Ensembl; ENST00000405308.6; ENSP00000385451.2; ENSG00000110492.17. [P21741-1]
DR Ensembl; ENST00000407067.1; ENSP00000384034.1; ENSG00000110492.17. [P21741-1]
DR GeneID; 4192; -.
DR KEGG; hsa:4192; -.
DR MANE-Select; ENST00000395566.9; ENSP00000378933.4; NM_002391.6; NP_002382.1.
DR UCSC; uc001nco.5; human. [P21741-1]
DR CTD; 4192; -.
DR DisGeNET; 4192; -.
DR GeneCards; MDK; -.
DR HGNC; HGNC:6972; MDK.
DR HPA; ENSG00000110492; Tissue enhanced (ovary).
DR MIM; 162096; gene.
DR neXtProt; NX_P21741; -.
DR OpenTargets; ENSG00000110492; -.
DR PharmGKB; PA30717; -.
DR VEuPathDB; HostDB:ENSG00000110492; -.
DR eggNOG; ENOG502S022; Eukaryota.
DR GeneTree; ENSGT00390000007640; -.
DR HOGENOM; CLU_136864_0_0_1; -.
DR InParanoid; P21741; -.
DR OMA; CKYKFGA; -.
DR OrthoDB; 1489280at2759; -.
DR PhylomeDB; P21741; -.
DR TreeFam; TF332376; -.
DR PathwayCommons; P21741; -.
DR Reactome; R-HSA-201556; Signaling by ALK.
DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus.
DR SignaLink; P21741; -.
DR SIGNOR; P21741; -.
DR BioGRID-ORCS; 4192; 21 hits in 1091 CRISPR screens.
DR ChiTaRS; MDK; human.
DR EvolutionaryTrace; P21741; -.
DR GeneWiki; Midkine; -.
DR GenomeRNAi; 4192; -.
DR Pharos; P21741; Tchem.
DR PRO; PR:P21741; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P21741; protein.
DR Bgee; ENSG00000110492; Expressed in ventricular zone and 99 other tissues.
DR ExpressionAtlas; P21741; baseline and differential.
DR Genevisible; P21741; HS.
DR GO; GO:0042995; C:cell projection; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0035374; F:chondroitin sulfate binding; ISS:UniProtKB.
DR GO; GO:0008083; F:growth factor activity; IBA:GO_Central.
DR GO; GO:1904399; F:heparan sulfate binding; IDA:UniProtKB.
DR GO; GO:0008201; F:heparin binding; IDA:UniProtKB.
DR GO; GO:0030325; P:adrenal gland development; ISS:UniProtKB.
DR GO; GO:0001662; P:behavioral fear response; IEA:Ensembl.
DR GO; GO:0030154; P:cell differentiation; NAS:UniProtKB.
DR GO; GO:0021681; P:cerebellar granular layer development; IEA:Ensembl.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0007010; P:cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0030421; P:defecation; IEA:Ensembl.
DR GO; GO:0021542; P:dentate gyrus development; IEA:Ensembl.
DR GO; GO:0044849; P:estrous cycle; ISS:UniProtKB.
DR GO; GO:0106091; P:glial cell projection elongation; ISS:UniProtKB.
DR GO; GO:0002232; P:leukocyte chemotaxis involved in inflammatory response; IMP:UniProtKB.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IMP:UniProtKB.
DR GO; GO:0007162; P:negative regulation of cell adhesion; ISS:UniProtKB.
DR GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0106015; P:negative regulation of inflammatory response to wounding; ISS:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:UniProtKB.
DR GO; GO:0030279; P:negative regulation of ossification; ISS:UniProtKB.
DR GO; GO:0045590; P:negative regulation of regulatory T cell differentiation; IMP:UniProtKB.
DR GO; GO:0007399; P:nervous system development; NAS:UniProtKB.
DR GO; GO:0048477; P:oogenesis; ISS:UniProtKB.
DR GO; GO:1905653; P:positive regulation of artery morphogenesis; ISS:UniProtKB.
DR GO; GO:1905555; P:positive regulation of blood vessel branching; IMP:UniProtKB.
DR GO; GO:0061036; P:positive regulation of cartilage development; ISS:UniProtKB.
DR GO; GO:0045785; P:positive regulation of cell adhesion; IDA:UniProtKB.
DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; IMP:UniProtKB.
DR GO; GO:2000347; P:positive regulation of hepatocyte proliferation; ISS:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0106016; P:positive regulation of inflammatory response to wounding; ISS:UniProtKB.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IMP:UniProtKB.
DR GO; GO:0010838; P:positive regulation of keratinocyte proliferation; IDA:UniProtKB.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; ISS:UniProtKB.
DR GO; GO:1903039; P:positive regulation of leukocyte cell-cell adhesion; IMP:UniProtKB.
DR GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; ISS:UniProtKB.
DR GO; GO:0010759; P:positive regulation of macrophage chemotaxis; IMP:UniProtKB.
DR GO; GO:2000179; P:positive regulation of neural precursor cell proliferation; ISS:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; IMP:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IDA:UniProtKB.
DR GO; GO:0090023; P:positive regulation of neutrophil chemotaxis; ISS:UniProtKB.
DR GO; GO:2000391; P:positive regulation of neutrophil extravasation; ISS:UniProtKB.
DR GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; IDA:UniProtKB.
DR GO; GO:0071673; P:positive regulation of smooth muscle cell chemotaxis; IMP:UniProtKB.
DR GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; ISS:UniProtKB.
DR GO; GO:0045582; P:positive regulation of T cell differentiation; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IEA:Ensembl.
DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; ISS:UniProtKB.
DR GO; GO:2000249; P:regulation of actin cytoskeleton reorganization; IDA:UniProtKB.
DR GO; GO:0050795; P:regulation of behavior; IEA:Ensembl.
DR GO; GO:0046850; P:regulation of bone remodeling; ISS:UniProtKB.
DR GO; GO:0032330; P:regulation of chondrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0010996; P:response to auditory stimulus; ISS:UniProtKB.
DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
DR GO; GO:0009611; P:response to wounding; ISS:UniProtKB.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0007614; P:short-term memory; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; NAS:ProtInc.
DR GO; GO:0002286; P:T cell activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0042246; P:tissue regeneration; ISS:UniProtKB.
DR Gene3D; 2.20.60.10; -; 1.
DR Gene3D; 2.30.90.10; -; 1.
DR InterPro; IPR000762; Midkine_heparin-bd_GF.
DR InterPro; IPR020090; PTN/MK_C_dom.
DR InterPro; IPR038130; PTN/MK_C_dom_sf.
DR InterPro; IPR020091; PTN/MK_diS_sf.
DR InterPro; IPR020089; PTN/MK_N_dom.
DR InterPro; IPR037122; PTN/MK_N_dom_sf.
DR InterPro; IPR020092; PTN_MK_heparin-bd_GF_CS.
DR PANTHER; PTHR13850; PTHR13850; 1.
DR Pfam; PF01091; PTN_MK_C; 1.
DR Pfam; PF05196; PTN_MK_N; 1.
DR PRINTS; PR00269; PTNMIDKINE.
DR SMART; SM00193; PTN; 1.
DR SUPFAM; SSF57288; SSF57288; 2.
DR PROSITE; PS00619; PTN_MK_1; 1.
DR PROSITE; PS00620; PTN_MK_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Developmental protein; Differentiation;
KW Direct protein sequencing; Disulfide bond; Growth factor; Heparin-binding;
KW Mitogen; Reference proteome; Secreted; Signal.
FT SIGNAL 1..20
FT /evidence="ECO:0000269|PubMed:15340161,
FT ECO:0000269|PubMed:1883381, ECO:0000269|PubMed:8241100"
FT CHAIN 21..143
FT /note="Midkine"
FT /id="PRO_0000024662"
FT SITE 103
FT /note="Required for high affinity binding to PTRZ1 by
FT interacting with the chondroitin sulfate chains of PTRZ1"
FT /evidence="ECO:0000250|UniProtKB:P12025"
FT DISULFID 37..61
FT DISULFID 45..70
FT DISULFID 52..74
FT DISULFID 84..116
FT DISULFID 94..126
FT VAR_SEQ 26..81
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17379400"
FT /id="VSP_047452"
FT VARIANT 21..22
FT /note="Missing (in 35% of the chains)"
FT /id="VAR_006353"
FT STRAND 29..31
FT /evidence="ECO:0007829|PDB:1MKN"
FT STRAND 38..43
FT /evidence="ECO:0007829|PDB:1MKN"
FT STRAND 48..54
FT /evidence="ECO:0007829|PDB:1MKN"
FT STRAND 57..63
FT /evidence="ECO:0007829|PDB:1MKN"
FT STRAND 66..68
FT /evidence="ECO:0007829|PDB:1MKN"
FT STRAND 76..79
FT /evidence="ECO:0007829|PDB:1MKN"
FT STRAND 96..100
FT /evidence="ECO:0007829|PDB:1MKC"
FT STRAND 111..115
FT /evidence="ECO:0007829|PDB:1MKC"
FT STRAND 118..120
FT /evidence="ECO:0007829|PDB:1MKC"
SQ SEQUENCE 143 AA; 15585 MW; 414A627FF39953C3 CRC64;
MQHRGFLLLT LLALLALTSA VAKKKDKVKK GGPGSECAEW AWGPCTPSSK DCGVGFREGT
CGAQTQRIRC RVPCNWKKEF GADCKYKFEN WGACDGGTGT KVRQGTLKKA RYNAQCQETI
RVTKPCTPKT KAKAKAKKGK GKD
