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 24-JUL-2024, entry version 205. 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 a cytokine and growth CC factor and mediates its signal through cell-surface proteoglycan and CC non-proteoglycan receptors (PubMed:10212223, PubMed:10772929, CC PubMed:12084985, PubMed:12122009, PubMed:12573468, PubMed:15466886, CC PubMed:18469519, PubMed:24458438). Binds cell-surface proteoglycan CC receptors via their chondroitin sulfate (CS) groups (PubMed:10212223, CC PubMed:12084985). 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:10212223, PubMed:10683378, PubMed:10772929, PubMed:12084985, CC PubMed:12122009, PubMed:12573468, PubMed:15466886, PubMed:22323540, CC PubMed:24458438). 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. DR RefSeq; XP_016873253.1; XM_017017764.1. 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; 80. DR DIP; DIP-5789N; -. DR IntAct; P21741; 46. DR STRING; 9606.ENSP00000385451; -. DR BindingDB; P21741; -. DR ChEMBL; CHEMBL1949490; -. DR GlyGen; P21741; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; P21741; -. DR PhosphoSitePlus; P21741; -. DR BioMuta; MDK; -. DR DMDM; 127116; -. DR jPOST; P21741; -. DR MassIVE; P21741; -. DR PaxDb; 9606-ENSP00000385451; -. DR PeptideAtlas; P21741; -. DR ProteomicsDB; 53896; -. [P21741-1] DR ProteomicsDB; 61338; -. DR Pumba; P21741; -. DR ABCD; P21741; 1 sequenced antibody. DR Antibodypedia; 4105; 639 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 AGR; HGNC:6972; -. 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; AECQTTV; -. DR OrthoDB; 4608966at2759; -. 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 Reactome; R-HSA-9851151; MDK and PTN in ALK signaling. DR SignaLink; P21741; -. DR SIGNOR; P21741; -. DR BioGRID-ORCS; 4192; 21 hits in 1169 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 100 other cell types or tissues. DR ExpressionAtlas; P21741; baseline and differential. 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:0035556; P:intracellular signal transduction; IDA: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:0045893; P:positive regulation of DNA-templated transcription; IEA:Ensembl. 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:1905564; P:positive regulation of vascular endothelial cell proliferation; ISS: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:0009611; P:response to wounding; ISS:UniProtKB. 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; Pleiotrophin/Midkine, N-terminal domain; 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:SF2; MIDKINE; 1. DR PANTHER; PTHR13850; PLEIOTROPHIN FAMILY MEMBER; 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; Midkine; 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 //