MK_RAT
ID MK_RAT Reviewed; 140 AA.
AC Q9R1S9;
DT 04-JAN-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 117.
DE RecName: Full=Midkine {ECO:0000303|PubMed:10683378, ECO:0000303|PubMed:11136554};
DE Short=MK {ECO:0000303|PubMed:10683378};
DE Flags: Precursor;
GN Name=Mdk {ECO:0000312|RGD:69073};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RC STRAIN=Sprague-Dawley; TISSUE=Kidney;
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 [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND DEVELOPMENTAL STAGE.
RC STRAIN=Sprague-Dawley; TISSUE=Fetal adrenal gland;
RX PubMed=11136554; DOI=10.1006/mgme.2000.3111;
RA Dewing P., Ching S.T., Zhang Y.-H., Huang B.-L., Peirce R.M.,
RA McCabe E.R.B., Vilain E.;
RT "Midkine is expressed early in rat fetal adrenal development.";
RL Mol. Genet. Metab. 71:616-622(2000).
RN [3]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
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).
CC -!- FUNCTION: Developmentally regulated, secreted growth factor homologous
CC to pleiotrophin (PTN), which has heparin binding activity. Binds
CC anaplastic lymphoma kinase (ALK) which induces ALK activation and
CC subsequent phosphorylation of the insulin receptor substrate (IRS1),
CC followed by the activation of mitogen-activated protein kinase (MAPK)
CC and PI3-kinase, and the induction of cell proliferation. Involved in
CC neointima formation after arterial injury, possibly by mediating
CC leukocyte recruitment. Also involved in early fetal adrenal gland
CC development (By similarity). {ECO:0000250, ECO:0000269|PubMed:10683378,
CC ECO:0000269|PubMed:11136554}.
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. Binds cell-surface proteoglycan receptors via
CC their chondroitin sulfate (CS) groups. Thereby regulates many processes
CC like inflammatory response, cell proliferation, cell adhesion, cell
CC growth, cell survival, tissue regeneration, cell differentiation and
CC cell migration. Participates in inflammatory processes by exerting two
CC different activities (By similarity). Firstly, mediates neutrophils and
CC macrophages recruitment to the sites of inflammation both by direct
CC action by cooperating namely with ITGB2 via LRP1 and by inducing
CC chemokine expression (PubMed:10683378). This inflammation can be
CC accompanied by epithelial cell survival and smooth muscle cell
CC migration after renal and vessel damage, respectively. Secondly,
CC suppresses the development of tolerogenic dendric cells thereby
CC inhibiting the differentiation of regulatory T cells and also promote T
CC cell expansion through NFAT signaling and Th1 cell differentiation (By
CC similarity). Promotes tissue regeneration after injury or trauma. After
CC heart damage negatively regulates the recruitment of inflammatory cells
CC and mediates cell survival through activation of anti-apoptotic
CC signaling pathways via MAPKs and AKT pathways through the activation of
CC angiogenesis. Also facilitates liver regeneration as well as bone
CC repair by recruiting macrophage at trauma site and by promoting
CC cartilage development by facilitating chondrocyte differentiation.
CC Plays a role in brain by promoting neural precursor cells survival and
CC growth through interaction with heparan sulfate proteoglycans (By
CC similarity). Binds PTPRZ1 and promotes neuronal migration and embryonic
CC neurons survival. Binds SDC3 or GPC2 and mediates neurite outgrowth and
CC cell adhesion. Binds chondroitin sulfate E and heparin leading to
CC inhibition of neuronal cell adhesion induced by binding with GPC2 (By
CC similarity). Binds CSPG5 and promotes elongation of oligodendroglial
CC precursor-like cells (By similarity). Also binds ITGA6:ITGB1 complex;
CC this interaction mediates MDK-induced neurite outgrowth. Binds LRP1;
CC promotes neuronal survival. Binds ITGA4:ITGB1 complex; this interaction
CC mediates MDK-induced osteoblast cells migration through PXN
CC phosphorylation. 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. Promotes epithelial to mesenchymal transition through
CC interaction with NOTCH2 (By similarity). During arteriogenesis, plays a
CC role in vascular endothelial cell proliferation by inducing VEGFA
CC expression and release which in turn induces nitric oxide synthase
CC expression. Moreover activates vasodilation through nitric oxide
CC synthase activation. Negatively regulates bone formation in response to
CC mechanical load by inhibiting Wnt/beta-catenin signaling in osteoblasts
CC (By similarity). In addition plays a role in hippocampal development,
CC working memory, auditory response, early fetal adrenal gland
CC development and the female reproductive system (By similarity)
CC (PubMed:11136554). {ECO:0000250|UniProtKB:P12025,
CC ECO:0000250|UniProtKB:P21741, ECO:0000269|PubMed:10683378,
CC ECO:0000269|PubMed:11136554}.
CC -!- SUBUNIT: Homodimer. Interacts with ALK. Interacts with LRP1; promotes
CC neuronal survival. Interacts with LRP2. Interacts with NCAM1. Interacts
CC (via C-terminal) with PTPRZ1 (via chondroitin sulfate chains); this
CC interaction is inhibited by PTN; this interaction promotes neuronal
CC migration. Interacts with NCL; this interaction promotes NCL clustering
CC and lateral movements of this complex into lipid rafts leading to MDK
CC internalization. Interacts with LRP6 and LRP8: this interaction is
CC calcium dependent. Interacts with ITGA4. Interacts with ITGA6.
CC Interacts with ITGB1. Interacts with ITGA4:ITGB1 complex; this
CC interaction mediates MDK-induced osteoblast cells migration through PXN
CC phosphorylation. Interacts with ITGA6:ITGB1 complex; this interaction
CC mediates MDK-induced neurite outgrowth. Interacts with NOTCH2; this
CC interactio mediates a nuclear accumulation of NOTCH2 and therefore
CC activation of NOTCH2 signaling leading to interaction between HES1 and
CC STAT3. Interacts with GPC2 (via heparan sulfate chain); this
CC interaction is inhibited by heparin followed by chondroitin sulfate E;
CC this interaction induces GPC2 clustering through heparan sulfate chain;
CC this interaction induces neuronal cell adhesion and neurite outgrowth.
CC Interacts with SDC3; this interaction induces SDC3 clustering; this
CC interaction induces neuronal cell adhesion and neurite outgrowth (By
CC similarity). Interacts with SDC1 (By similarity). Interacts with CSPG5;
CC this interaction promotes elongation of oligodendroglial precursor-like
CC cells (By similarity). {ECO:0000250|UniProtKB:P12025,
CC ECO:0000250|UniProtKB:P21741}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Expressed at a low level in arteries, and at higher
CC levels in newly formed neointima. In brain, expressed in the caudate
CC nucleus and the brain stem. {ECO:0000269|PubMed:10683378,
CC ECO:0000269|PubMed:1768439}.
CC -!- DEVELOPMENTAL STAGE: In the cortices of the adrenal glands, expressed
CC at 12.5 dpc, decreases considerably at 15.5 dpc and is almost
CC undetectable in the newborn stage. In brain, expressed at low levels in
CC early embryos, expression peaks between E12 and E14, and rapidly falls
CC until birth when expression is barely detectable.
CC {ECO:0000269|PubMed:11136554, ECO:0000269|PubMed:1768439}.
CC -!- INDUCTION: In arteries 3 days after injury. Expression continues to
CC increase until day 7 after injury and decreases slightly by day 14.
CC {ECO:0000269|PubMed:10683378}.
CC -!- SIMILARITY: Belongs to the pleiotrophin family. {ECO:0000305}.
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DR EMBL; AB025023; BAA83783.1; -; mRNA.
DR EMBL; AF315950; AAG45151.1; -; mRNA.
DR RefSeq; NP_110486.1; NM_030859.2.
DR RefSeq; XP_006234654.1; XM_006234592.2.
DR RefSeq; XP_006234655.1; XM_006234593.3.
DR AlphaFoldDB; Q9R1S9; -.
DR SMR; Q9R1S9; -.
DR BioGRID; 249514; 4.
DR IntAct; Q9R1S9; 1.
DR STRING; 10116.ENSRNOP00000036207; -.
DR PaxDb; Q9R1S9; -.
DR PRIDE; Q9R1S9; -.
DR GeneID; 81517; -.
DR KEGG; rno:81517; -.
DR UCSC; RGD:69073; rat.
DR CTD; 4192; -.
DR RGD; 69073; Mdk.
DR VEuPathDB; HostDB:ENSRNOG00000017560; -.
DR eggNOG; ENOG502S022; Eukaryota.
DR HOGENOM; CLU_136864_0_0_1; -.
DR InParanoid; Q9R1S9; -.
DR OMA; CASKMKS; -.
DR OrthoDB; 1489280at2759; -.
DR PhylomeDB; Q9R1S9; -.
DR Reactome; R-RNO-201556; Signaling by ALK.
DR PRO; PR:Q9R1S9; -.
DR Proteomes; UP000002494; Chromosome 3.
DR Bgee; ENSRNOG00000017560; Expressed in ovary and 19 other tissues.
DR ExpressionAtlas; Q9R1S9; baseline and differential.
DR Genevisible; Q9R1S9; RN.
DR GO; GO:0042995; C:cell projection; IDA:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
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; ISS:UniProtKB.
DR GO; GO:0008201; F:heparin binding; ISS:UniProtKB.
DR GO; GO:0030325; P:adrenal gland development; IDA:UniProtKB.
DR GO; GO:0001662; P:behavioral fear response; ISO:RGD.
DR GO; GO:0016477; P:cell migration; IDA:RGD.
DR GO; GO:0021681; P:cerebellar granular layer development; ISO:RGD.
DR GO; GO:0021987; P:cerebral cortex development; ISO:RGD.
DR GO; GO:0007010; P:cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0030421; P:defecation; ISO:RGD.
DR GO; GO:0021542; P:dentate gyrus development; ISO:RGD.
DR GO; GO:0044849; P:estrous cycle; ISS:UniProtKB.
DR GO; GO:0106091; P:glial cell projection elongation; ISS:UniProtKB.
DR GO; GO:0021766; P:hippocampus development; ISO:RGD.
DR GO; GO:0002232; P:leukocyte chemotaxis involved in inflammatory response; ISS: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; ISS: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; ISS:UniProtKB.
DR GO; GO:1901215; P:negative regulation of neuron death; ISO:RGD.
DR GO; GO:0030279; P:negative regulation of ossification; ISS:UniProtKB.
DR GO; GO:0045590; P:negative regulation of regulatory T cell differentiation; ISS: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; ISS:UniProtKB.
DR GO; GO:0061036; P:positive regulation of cartilage development; ISS:UniProtKB.
DR GO; GO:0045785; P:positive regulation of cell adhesion; ISS:UniProtKB.
DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:UniProtKB.
DR GO; GO:2000347; P:positive regulation of hepatocyte proliferation; ISS:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISS: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; ISS:UniProtKB.
DR GO; GO:0010838; P:positive regulation of keratinocyte proliferation; ISS: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; ISS:UniProtKB.
DR GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; ISS:UniProtKB.
DR GO; GO:0010759; P:positive regulation of macrophage chemotaxis; ISS: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; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISS: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; ISS:UniProtKB.
DR GO; GO:0071673; P:positive regulation of smooth muscle cell chemotaxis; ISS: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; ISO:RGD.
DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; ISS:UniProtKB.
DR GO; GO:2000249; P:regulation of actin cytoskeleton reorganization; ISS:UniProtKB.
DR GO; GO:0050795; P:regulation of behavior; ISO:RGD.
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; IEP:RGD.
DR GO; GO:0009725; P:response to hormone; IEP:RGD.
DR GO; GO:0009611; P:response to wounding; IDA:UniProtKB.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0007614; P:short-term memory; ISO:RGD.
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 2: Evidence at transcript level;
KW Developmental protein; Differentiation; Disulfide bond; Growth factor;
KW Heparin-binding; Mitogen; Reference proteome; Secreted; Signal.
FT SIGNAL 1..20
FT /evidence="ECO:0000250"
FT CHAIN 21..140
FT /note="Midkine"
FT /id="PRO_0000024664"
FT SITE 100
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 34..58
FT /evidence="ECO:0000250"
FT DISULFID 42..67
FT /evidence="ECO:0000250"
FT DISULFID 49..71
FT /evidence="ECO:0000250"
FT DISULFID 81..113
FT /evidence="ECO:0000250"
FT DISULFID 91..123
FT /evidence="ECO:0000250"
SQ SEQUENCE 140 AA; 15406 MW; 10E340C43AA619CA CRC64;
MQHRSFFLLA LVALLAVTTA VAKKKDKVKK GSECSEWTWG PCTPSSKDCG MGFREGTCGA
QTQRIHCKVP CNWKKEFGAD CKYKFESWGA CDGSTGTKAR QGTLKKARYN AQCQETIRVT
KPCTSKTKSK AKAKKGKGKD
