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Midkine (MK) (Retanoic acid-responsive protein) (Retinoic acid-induced differentiation factor)

 MK_MOUSE                Reviewed;         140 AA.
P12025;
01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
01-AUG-1991, sequence version 2.
02-JUN-2021, entry version 158.
RecName: Full=Midkine {ECO:0000303|PubMed:8827451};
Short=MK {ECO:0000303|PubMed:2345177};
AltName: Full=Retanoic acid-responsive protein {ECO:0000303|PubMed:2355021};
AltName: Full=Retinoic acid-induced differentiation factor;
Flags: Precursor;
Name=Mdk {ECO:0000312|MGI:MGI:96949}; Synonyms=Mk;
Mus musculus (Mouse).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
Murinae; Mus; Mus.
NCBI_TaxID=10090;
[1]
NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND INDUCTION.
PubMed=2345177;
Matsubara S., Tomomura M., Kadomatsu K., Muramatsu T.;
"Structure of a retinoic acid-responsive gene, MK, which is transiently
activated during the differentiation of embryonal carcinoma cells and the
mid-gestation period of mouse embryogenesis.";
J. Biol. Chem. 265:9441-9443(1990).
[2]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=2355021;
Tomomura M., Kadomatsu K., Matsubara S., Muramatsu T.;
"A retinoic acid-responsive gene, MK, found in the teratocarcinoma system.
Heterogeneity of the transcript and the nature of the translation
product.";
J. Biol. Chem. 265:10765-10770(1990).
[3]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=3355557; DOI=10.1016/s0006-291x(88)80505-9;
Kadomatsu K., Tomomura M., Muramatsu T.;
"cDNA cloning and sequencing of a new gene intensely expressed in early
differentiation stages of embryonal carcinoma cells and in mid-gestation
period of mouse embryogenesis.";
Biochem. Biophys. Res. Commun. 151:1312-1318(1988).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
STRAIN=FVB/N; TISSUE=Salivary gland;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project:
the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[5]
NUCLEOTIDE SEQUENCE OF 1-42.
PubMed=8827451; DOI=10.1093/oxfordjournals.jbchem.a021361;
Kaneda N., Talukder A.H., Nishiyama H., Koizumi S., Muramatsu T.;
"Midkine, a heparin-binding growth/differentiation factor, exhibits nerve
cell adhesion and guidance activity for neurite outgrowth in vitro.";
J. Biochem. 119:1150-1156(1996).
[6]
INTERACTION WITH SDC1 AND SDC3.
PubMed=9089390;
Nakanishi T., Kadomatsu K., Okamoto T., Ichihara-Tanaka K., Kojima T.,
Saito H., Tomoda Y., Muramatsu T.;
"Expression of syndecan-1 and -3 during embryogenesis of the central
nervous system in relation to binding with midkine.";
J. Biochem. 121:197-205(1997).
[7]
DISRUPTION PHENOTYPE, AND FUNCTION.
PubMed=10096022; DOI=10.1046/j.1365-2443.1998.00231.x;
Nakamura E., Kadomatsu K., Yuasa S., Muramatsu H., Mamiya T., Nabeshima T.,
Fan Q.W., Ishiguro K., Igakura T., Matsubara S., Kaname T., Horiba M.,
Saito H., Muramatsu T.;
"Disruption of the midkine gene (Mdk) resulted in altered expression of a
calcium binding protein in the hippocampus of infant mice and their
abnormal behaviour.";
Genes Cells 3:811-822(1998).
[8]
MUTAGENESIS OF ARG-100; LYS-105 AND LYS-106, INTERACTION WITH PTPRZ1, AND
SITE.
PubMed=10212223; DOI=10.1074/jbc.274.18.12474;
Maeda N., Ichihara-Tanaka K., Kimura T., Kadomatsu K., Muramatsu T.,
Noda M.;
"A receptor-like protein-tyrosine phosphatase PTPzeta/RPTPbeta binds a
heparin-binding growth factor midkine. Involvement of arginine 78 of
midkine in the high affinity binding to PTPzeta.";
J. Biol. Chem. 274:12474-12479(1999).
[9]
FUNCTION.
PubMed=10978312; DOI=10.1074/jbc.m002538200;
Ueoka C., Kaneda N., Okazaki I., Nadanaka S., Muramatsu T., Sugahara K.;
"Neuronal cell adhesion, mediated by the heparin-binding neuroregulatory
factor midkine, is specifically inhibited by chondroitin sulfate E.
Structural ans functional implications of the over-sulfated chondroitin
sulfate.";
J. Biol. Chem. 275:37407-37413(2000).
[10]
FUNCTION.
PubMed=10683378; DOI=10.1172/jci7208;
Horiba M., Kadomatsu K., Nakamura E., Muramatsu H., Ikematsu S., Sakuma S.,
Hayashi K., Yuzawa Y., Matsuo S., Kuzuya M., Kaname T., Hirai M., Saito H.,
Muramatsu T.;
"Neointima formation in a restenosis model is suppressed in midkine-
deficient mice.";
J. Clin. Invest. 105:489-495(2000).
[11]
INTERACTION WITH SDC3.
PubMed=12084985; DOI=10.1023/a:1016042303253;
Kurosawa N., Chen G.Y., Kadomatsu K., Ikematsu S., Sakuma S., Muramatsu T.;
"Glypican-2 binds to midkine: the role of glypican-2 in neuronal cell
adhesion and neurite outgrowth.";
Glycoconj. J. 18:499-507(2001).
[12]
FUNCTION.
PubMed=15509530; DOI=10.1016/s0002-9440(10)63417-7;
Kawai H., Sato W., Yuzawa Y., Kosugi T., Matsuo S., Takei Y., Kadomatsu K.,
Muramatsu T.;
"Lack of the growth factor midkine enhances survival against cisplatin-
induced renal damage.";
Am. J. Pathol. 165:1603-1612(2004).
[13]
FUNCTION.
PubMed=15482347; DOI=10.1111/j.1478-3231.2004.0990.x;
Ochiai K., Muramatsu H., Yamamoto S., Ando H., Muramatsu T.;
"The role of midkine and pleiotrophin in liver regeneration.";
Liver Int. 24:484-491(2004).
[14]
FUNCTION, AND INDUCTION.
PubMed=17015789; DOI=10.1161/circulationaha.106.632273;
Horiba M., Kadomatsu K., Yasui K., Lee J.K., Takenaka H., Sumida A.,
Kamiya K., Chen S., Sakuma S., Muramatsu T., Kodama I.;
"Midkine plays a protective role against cardiac ischemia/reperfusion
injury through a reduction of apoptotic reaction.";
Circulation 114:1713-1720(2006).
[15]
DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND FUNCTION.
PubMed=17121547; DOI=10.1111/j.1365-2443.2006.01028.x;
Muramatsu H., Zou P., Kurosawa N., Ichihara-Tanaka K., Maruyama K.,
Inoh K., Sakai T., Chen L., Sato M., Muramatsu T.;
"Female infertility in mice deficient in midkine and pleiotrophin, which
form a distinct family of growth factors.";
Genes Cells 11:1405-1417(2006).
[16]
INTERACTION WITH CSPG5, AND FUNCTION.
PubMed=16901907; DOI=10.1074/jbc.m602228200;
Ichihara-Tanaka K., Oohira A., Rumsby M., Muramatsu T.;
"Neuroglycan C is a novel midkine receptor involved in process elongation
of oligodendroglial precursor-like cells.";
J. Biol. Chem. 281:30857-30864(2006).
[17]
FUNCTION.
PubMed=17230638; DOI=10.1111/j.1471-4159.2006.04138.x;
Zou P., Muramatsu H., Miyata T., Muramatsu T.;
"Midkine, a heparin-binding growth factor, is expressed in neural precursor
cells and promotes their growth.";
J. Neurochem. 99:1470-1479(2006).
[18]
DISRUPTION PHENOTYPE, AND FUNCTION.
PubMed=16619002; DOI=10.1038/labinvest.3700428;
Zou P., Muramatsu H., Sone M., Hayashi H., Nakashima T., Muramatsu T.;
"Mice doubly deficient in the midkine and pleiotrophin genes exhibit
deficits in the expression of beta-tectorin gene and in auditory
response.";
Lab. Invest. 86:645-653(2006).
[19]
FUNCTION, AND INDUCTION.
PubMed=19060126; DOI=10.1152/ajpheart.00733.2008;
Takenaka H., Horiba M., Ishiguro H., Sumida A., Hojo M., Usui A., Akita T.,
Sakuma S., Ueda Y., Kodama I., Kadomatsu K.;
"Midkine prevents ventricular remodeling and improves long-term survival
after myocardial infarction.";
Am. J. Physiol. 296:H462-H469(2009).
[20]
DISRUPTION PHENOTYPE, AND FUNCTION.
PubMed=20200993; DOI=10.1002/jbmr.75;
Neunaber C., Catala-Lehnen P., Beil F.T., Marshall R.P., Kanbach V.,
Baranowsky A., Lehmann W., Streichert T., Ignatius A., Muramatsu T.,
Schinke T., Amling M.;
"Increased trabecular bone formation in mice lacking the growth factor
midkine.";
J. Bone Miner. Res. 25:1724-1735(2010).
[21]
FUNCTION.
PubMed=21185956; DOI=10.1016/j.bone.2010.12.019;
Liedert A., Mattausch L., Roentgen V., Blakytny R., Vogele D., Pahl M.,
Bindl R., Neunaber C., Schinke T., Harroch S., Amling M., Ignatius A.;
"Midkine-deficiency increases the anabolic response of cortical bone to
mechanical loading.";
Bone 48:945-951(2011).
[22]
INDUCTION.
PubMed=22323540; DOI=10.4049/jimmunol.1102346;
Sonobe Y., Li H., Jin S., Kishida S., Kadomatsu K., Takeuchi H., Mizuno T.,
Suzumura A.;
"Midkine inhibits inducible regulatory T cell differentiation by
suppressing the development of tolerogenic dendritic cells.";
J. Immunol. 188:2602-2611(2012).
[23]
FUNCTION.
PubMed=24458438; DOI=10.1182/blood-2013-06-510875;
Weckbach L.T., Gola A., Winkelmann M., Jakob S.M., Groesser L.,
Borgolte J., Pogoda F., Pick R., Pruenster M., Mueller-Hoecker J.,
Deindl E., Sperandio M., Walzog B.;
"The cytokine midkine supports neutrophil trafficking during acute
inflammation by promoting adhesion via beta2 integrins (CD11/CD18).";
Blood 123:1887-1896(2014).
[24]
INDUCTION, AND FUNCTION.
PubMed=25551381; DOI=10.1371/journal.pone.0116282;
Haffner-Luntzer M., Heilmann A., Rapp A.E., Beie S., Schinke T., Amling M.,
Ignatius A., Liedert A.;
"Midkine-deficiency delays chondrogenesis during the early phase of
fracture healing in mice.";
PLoS ONE 9:E116282-E116282(2014).
[25]
FUNCTION.
PubMed=28183532; DOI=10.1016/j.ajpath.2016.12.006;
Masuda T., Maeda K., Sato W., Kosugi T., Sato Y., Kojima H., Kato N.,
Ishimoto T., Tsuboi N., Uchimura K., Yuzawa Y., Maruyama S., Kadomatsu K.;
"Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of
Activated T Cells Signaling and Th1 Cell Differentiation in Lupus
Nephritis.";
Am. J. Pathol. 187:740-751(2017).
[26]
FUNCTION.
PubMed=29233575; DOI=10.1016/j.ebiom.2017.11.020;
Lautz T., Lasch M., Borgolte J., Troidl K., Pagel J.I.,
Caballero-Martinez A., Kleinert E.C., Walzog B., Deindl E.;
"Midkine Controls Arteriogenesis by Regulating the Bioavailability of
Vascular Endothelial Growth Factor A and the Expression of Nitric Oxide
Synthase 1 and 3.";
EBioMedicine 27:237-246(2018).
-!- FUNCTION: Secreted protein that functions as cytokine and growth factor
and mediates its signal through cell-surface proteoglycan and non-
proteoglycan receptors (PubMed:16901907). Binds cell-surface
proteoglycan receptors via their chondroitin sulfate (CS) groups
(PubMed:17230638). Thereby regulates many processes like inflammatory
response, cell proliferation, cell adhesion, cell growth, cell
survival, tissue regeneration, cell differentiation and cell migration
(PubMed:17230638, PubMed:19060126, PubMed:17015789, PubMed:28183532,
PubMed:10683378, PubMed:15482347, PubMed:15509530, PubMed:24458438,
PubMed:25551381, PubMed:29233575). Participates in inflammatory
processes by exerting two different activities. Firstly, mediates
neutrophils and macrophages recruitment to the sites of inflammation
both by direct action by cooperating namely with ITGB2 via LRP1 and by
inducing chemokine expression (PubMed:10683378, PubMed:15509530,
PubMed:24458438, PubMed:28183532). This inflammation can be accompanied
by epithelial cell survival and smooth muscle cell migration after
renal and vessel damage, respectively (PubMed:15509530,
PubMed:10683378). Secondly, suppresses the development of tolerogenic
dendric cells thereby inhibiting the differentiation of regulatory T
cells and also promote T cell expansion through NFAT signaling and Th1
cell differentiation (PubMed:28183532). Promotes tissue regeneration
after injury or trauma. After heart damage negatively regulates the
recruitment of inflammatory cells and mediates cell survival through
activation of anti-apoptotic signaling pathways via MAPKs and AKT
pathways through the activation of angiogenesis (PubMed:17015789,
PubMed:19060126). Also facilitates liver regeneration as well as bone
repair by recruiting macrophage at trauma site and by promoting
cartilage development by facilitating chondrocyte differentiation
(PubMed:15482347, PubMed:25551381). Plays a role in brain by promoting
neural precursor cells survival and growth through interaction with
heparan sulfate proteoglycans (PubMed:17230638). Binds PTPRZ1 and
promotes neuronal migration and embryonic neurons survival (By
similarity). Binds SDC3 or GPC2 and mediates neurite outgrowth and cell
adhesion (By similarity). Binds chondroitin sulfate E and heparin
leading to inhibition of neuronal cell adhesion induced by binding with
GPC2 (PubMed:10978312). Binds CSPG5 and promotes elongation of
oligodendroglial precursor-like cells (PubMed:16901907). Also binds
ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite
outgrowth (By similarity). Binds LRP1; promotes neuronal survival (By
similarity). Binds ITGA4:ITGB1 complex; this interaction mediates MDK-
induced osteoblast cells migration through PXN phosphorylation (By
similarity). 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 (By similarity). Promotes epithelial to mesenchymal
transition through interaction with NOTCH2 (By similarity). During
arteriogenesis, plays a role in vascular endothelial cell proliferation
by inducing VEGFA expression and release which in turn induces nitric
oxide synthase expression. Moreover activates vasodilation through
nitric oxide synthase activation (PubMed:29233575). Negatively
regulates bone formation in response to mechanical load by inhibiting
Wnt/beta-catenin signaling in osteoblasts (PubMed:21185956,
PubMed:20200993). In addition plays a role in hippocampal development,
working memory, auditory response, early fetal adrenal gland
development and the female reproductive system (PubMed:16619002,
PubMed:17121547, PubMed:10096022). {ECO:0000250|UniProtKB:P21741,
ECO:0000269|PubMed:10096022, ECO:0000269|PubMed:10683378,
ECO:0000269|PubMed:10978312, ECO:0000269|PubMed:15482347,
ECO:0000269|PubMed:15509530, ECO:0000269|PubMed:16619002,
ECO:0000269|PubMed:16901907, ECO:0000269|PubMed:17015789,
ECO:0000269|PubMed:17121547, ECO:0000269|PubMed:17230638,
ECO:0000269|PubMed:19060126, ECO:0000269|PubMed:20200993,
ECO:0000269|PubMed:21185956, ECO:0000269|PubMed:24458438,
ECO:0000269|PubMed:25551381, ECO:0000269|PubMed:28183532,
ECO:0000269|PubMed:29233575}.
-!- SUBUNIT: Homodimer. Interacts with ALK. Interacts with LRP1; promotes
neuronal survival. Interacts with LRP2. Interacts with NCAM1 (By
similarity). Interacts (via C-terminal) with PTPRZ1 (via chondroitin
sulfate chains); this interaction is inhibited by PTN; this interaction
promotes neuronal migration (PubMed:10212223). Interacts with NCL; this
interaction promotes NCL clustering and lateral movements of this
complex into lipid rafts leading to MDK internalization. Interacts with
LRP6 and LRP8: this interaction is calcium dependent. Interacts with
ITGA4. Interacts with ITGA6. Interacts with ITGB1. Interacts with
ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast
cells migration through PXN phosphorylation. Interacts with ITGA6:ITGB1
complex; this interaction mediates MDK-induced neurite outgrowth.
Interacts with NOTCH2; this interactio mediates a nuclear accumulation
of NOTCH2 and therefore activation of NOTCH2 signaling leading to
interaction between HES1 and STAT3. Interacts with GPC2 (via heparan
sulfate chain); this interaction is inhibited by heparin followed by
chondroitin sulfate E; this interaction induces GPC2 clustering through
heparan sulfate chain; this interaction induces neuronal cell adhesion
and neurite outgrowth (By similarity). Interacts with SDC3; this
interaction induces SDC3 clustering; this interaction induces neuronal
cell adhesion and neurite outgrowth (PubMed:9089390, PubMed:12084985).
Interacts with SDC1 (PubMed:9089390). Interacts with CSPG5; this
interaction promotes elongation of oligodendroglial precursor-like
cells (PubMed:16901907). {ECO:0000250|UniProtKB:P21741,
ECO:0000269|PubMed:10212223, ECO:0000269|PubMed:12084985,
ECO:0000269|PubMed:16901907, ECO:0000269|PubMed:9089390}.
-!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
-!- TISSUE SPECIFICITY: Expressed in the follicular epithelium and
granulosa cells of the ovary. {ECO:0000269|PubMed:17121547}.
-!- DEVELOPMENTAL STAGE: Is expressed temporarily during the early stages
of retinoic acid-induced differentiation of embryonal carcinoma cells
and during the mid-gestation period of mouse embryogenesis. In late
embryos and in adults expression is restricted to the kidney.
-!- INDUCTION: By retinoic acid (PubMed:2345177). Induced after tissue
damage (PubMed:17015789, PubMed:19060126). Induced by inflammatory
cells, in particular, CD4(+) T cells under inflammatory conditions
(PubMed:22323540). Induced during the early and intermediate phase of
fracture repair (PubMed:25551381). {ECO:0000269|PubMed:17015789,
ECO:0000269|PubMed:19060126, ECO:0000269|PubMed:22323540,
ECO:0000269|PubMed:2345177, ECO:0000269|PubMed:25551381}.
-!- DISRUPTION PHENOTYPE: Homozygous knockout MDK mice are viable and
reproduce normally. Mice have no apparent abnormalities except that
postnatal development of the hippocampus is delayed. However 4 weeks
after birth, mice have a deficit in their working memory and have an
increased anxiety (PubMed:10096022). Knockout MDK mice exhibit low to
moderate levels of auditory deficits and generally respond at around 50
dB. PTN and MDK double knockoutmice have a deficit of auditory response
(PubMed:16619002). PTN and MDK double knockout mice are born in only
one third the number expected by Mendelian segregation and 4 weeks
after birth weigh about half as much as wild-type mice. Most of the
female are infertile. Both male and female one-month-old mice show a
defect in spontaneous locomotive activity of 50-60% of that of wild-
type mice. Although the difference in activity decrease with age, the
activity of 3-month-old male double knockout mice is still about 80% of
that of the wild-type mice. The diestrus and proestrus periods are long
and the estrus period is short. Furthermore, vaginal abnormality is
found in about half of the double deficient mice (PubMed:17121547).
Homozygous knockout MDK mice display not significant difference from
wild-type until the age of 6 month. Mice at 12 and 18 months of age
show an increased trabecular bone volume, accompanied by cortical
porosity (PubMed:20200993). {ECO:0000269|PubMed:10096022,
ECO:0000269|PubMed:16619002, ECO:0000269|PubMed:17121547,
ECO:0000269|PubMed:20200993}.
-!- SIMILARITY: Belongs to the pleiotrophin family. {ECO:0000305}.
---------------------------------------------------------------------------
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EMBL; M19662; AAA39710.1; -; mRNA.
EMBL; M34327; AAA39712.1; -; mRNA.
EMBL; M34328; AAA39715.1; -; mRNA.
EMBL; M35833; AAA39714.1; -; mRNA.
EMBL; M34094; AAA39717.1; -; Genomic_DNA.
EMBL; BC012244; AAH12244.1; -; mRNA.
CCDS; CCDS16440.1; -.
PIR; A27684; A27684.
PIR; A35305; A35305.
RefSeq; NP_001012335.1; NM_001012335.2.
RefSeq; NP_001012336.1; NM_001012336.2.
RefSeq; NP_001278410.1; NM_001291481.1.
RefSeq; NP_034914.1; NM_010784.5.
BioGRID; 201369; 3.
DIP; DIP-5791N; -.
IntAct; P12025; 3.
STRING; 10090.ENSMUSP00000028672; -.
iPTMnet; P12025; -.
PhosphoSitePlus; P12025; -.
MaxQB; P12025; -.
PaxDb; P12025; -.
PeptideAtlas; P12025; -.
PRIDE; P12025; -.
ProteomicsDB; 290257; -.
Antibodypedia; 4105; 584 antibodies.
DNASU; 17242; -.
Ensembl; ENSMUST00000028672; ENSMUSP00000028672; ENSMUSG00000027239.
Ensembl; ENSMUST00000069423; ENSMUSP00000068413; ENSMUSG00000027239.
Ensembl; ENSMUST00000090602; ENSMUSP00000088090; ENSMUSG00000027239.
Ensembl; ENSMUST00000111309; ENSMUSP00000106941; ENSMUSG00000027239.
GeneID; 17242; -.
KEGG; mmu:17242; -.
UCSC; uc008kww.2; mouse.
CTD; 4192; -.
MGI; MGI:96949; Mdk.
eggNOG; ENOG502S022; Eukaryota.
GeneTree; ENSGT00390000007640; -.
HOGENOM; CLU_136864_0_0_1; -.
InParanoid; P12025; -.
OMA; FETWGAC; -.
OrthoDB; 1489280at2759; -.
PhylomeDB; P12025; -.
TreeFam; TF332376; -.
BioGRID-ORCS; 17242; 0 hits in 52 CRISPR screens.
ChiTaRS; Mdk; mouse.
PRO; PR:P12025; -.
Proteomes; UP000000589; Chromosome 2.
RNAct; P12025; protein.
Bgee; ENSMUSG00000027239; Expressed in limb and 156 other tissues.
Genevisible; P12025; MM.
GO; GO:0042995; C:cell projection; ISO:MGI.
GO; GO:0005737; C:cytoplasm; ISO:MGI.
GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
GO; GO:0035374; F:chondroitin sulfate binding; IDA:UniProtKB.
GO; GO:0008083; F:growth factor activity; IBA:GO_Central.
GO; GO:1904399; F:heparan sulfate binding; ISS:UniProtKB.
GO; GO:0008201; F:heparin binding; IDA:UniProtKB.
GO; GO:0030325; P:adrenal gland development; ISS:UniProtKB.
GO; GO:0001662; P:behavioral fear response; IMP:DFLAT.
GO; GO:0016477; P:cell migration; ISO:MGI.
GO; GO:0021681; P:cerebellar granular layer development; IMP:DFLAT.
GO; GO:0021987; P:cerebral cortex development; IEP:DFLAT.
GO; GO:0007010; P:cytoskeleton organization; IMP:UniProtKB.
GO; GO:0030421; P:defecation; IMP:DFLAT.
GO; GO:0021542; P:dentate gyrus development; IEP:DFLAT.
GO; GO:0044849; P:estrous cycle; IMP:UniProtKB.
GO; GO:0106091; P:glial cell projection elongation; IDA:UniProtKB.
GO; GO:0021766; P:hippocampus development; IMP:DFLAT.
GO; GO:0002232; P:leukocyte chemotaxis involved in inflammatory response; IMP:UniProtKB.
GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:UniProtKB.
GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IMP:UniProtKB.
GO; GO:0007162; P:negative regulation of cell adhesion; IDA:UniProtKB.
GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; IMP:UniProtKB.
GO; GO:0106015; P:negative regulation of inflammatory response to wounding; IMP:UniProtKB.
GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:DFLAT.
GO; GO:1901215; P:negative regulation of neuron death; IDA:DFLAT.
GO; GO:0030279; P:negative regulation of ossification; IMP:UniProtKB.
GO; GO:0045590; P:negative regulation of regulatory T cell differentiation; ISS:UniProtKB.
GO; GO:0048477; P:oogenesis; IMP:UniProtKB.
GO; GO:1905653; P:positive regulation of artery morphogenesis; IMP:UniProtKB.
GO; GO:1905555; P:positive regulation of blood vessel branching; ISS:UniProtKB.
GO; GO:0061036; P:positive regulation of cartilage development; IMP:UniProtKB.
GO; GO:0045785; P:positive regulation of cell adhesion; ISS:UniProtKB.
GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:UniProtKB.
GO; GO:2000347; P:positive regulation of hepatocyte proliferation; IMP:UniProtKB.
GO; GO:0050729; P:positive regulation of inflammatory response; ISS:UniProtKB.
GO; GO:0106016; P:positive regulation of inflammatory response to wounding; IMP:UniProtKB.
GO; GO:0032735; P:positive regulation of interleukin-12 production; ISS:UniProtKB.
GO; GO:0010838; P:positive regulation of keratinocyte proliferation; ISS:UniProtKB.
GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IMP:UniProtKB.
GO; GO:1903039; P:positive regulation of leukocyte cell-cell adhesion; ISS:UniProtKB.
GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; IMP:UniProtKB.
GO; GO:0010759; P:positive regulation of macrophage chemotaxis; IMP:UniProtKB.
GO; GO:2000179; P:positive regulation of neural precursor cell proliferation; IMP:UniProtKB.
GO; GO:2001224; P:positive regulation of neuron migration; ISS:UniProtKB.
GO; GO:0010976; P:positive regulation of neuron projection development; ISS:UniProtKB.
GO; GO:0090023; P:positive regulation of neutrophil chemotaxis; IMP:UniProtKB.
GO; GO:2000391; P:positive regulation of neutrophil extravasation; IMP:UniProtKB.
GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; ISS:UniProtKB.
GO; GO:0071673; P:positive regulation of smooth muscle cell chemotaxis; ISS:UniProtKB.
GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; IMP:UniProtKB.
GO; GO:0045582; P:positive regulation of T cell differentiation; IMP:UniProtKB.
GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:DFLAT.
GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; IMP:UniProtKB.
GO; GO:2000249; P:regulation of actin cytoskeleton reorganization; ISS:UniProtKB.
GO; GO:0050795; P:regulation of behavior; IMP:DFLAT.
GO; GO:0046850; P:regulation of bone remodeling; IMP:UniProtKB.
GO; GO:0032330; P:regulation of chondrocyte differentiation; IMP:UniProtKB.
GO; GO:0010996; P:response to auditory stimulus; IMP:UniProtKB.
GO; GO:0042493; P:response to drug; IEA:Ensembl.
GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
GO; GO:0009611; P:response to wounding; IDA:UniProtKB.
GO; GO:0007614; P:short-term memory; IMP:DFLAT.
GO; GO:0002286; P:T cell activation involved in immune response; IMP:UniProtKB.
GO; GO:0042246; P:tissue regeneration; IMP:UniProtKB.
Gene3D; 2.20.60.10; -; 1.
Gene3D; 2.30.90.10; -; 1.
InterPro; IPR000762; Midkine_heparin-bd_GF.
InterPro; IPR020090; PTN/MK_C_dom.
InterPro; IPR038130; PTN/MK_C_dom_sf.
InterPro; IPR020091; PTN/MK_diS_sf.
InterPro; IPR020089; PTN/MK_N_dom.
InterPro; IPR037122; PTN/MK_N_dom_sf.
InterPro; IPR020092; PTN_MK_heparin-bd_GF_CS.
PANTHER; PTHR13850; PTHR13850; 1.
Pfam; PF01091; PTN_MK_C; 1.
Pfam; PF05196; PTN_MK_N; 1.
PRINTS; PR00269; PTNMIDKINE.
SMART; SM00193; PTN; 1.
SUPFAM; SSF57288; SSF57288; 2.
PROSITE; PS00619; PTN_MK_1; 1.
PROSITE; PS00620; PTN_MK_2; 1.
1: Evidence at protein level;
Developmental protein; Differentiation; Disulfide bond; Growth factor;
Heparin-binding; Mitogen; Reference proteome; Secreted; Signal.
SIGNAL 1..22
/evidence="ECO:0000255"
CHAIN 23..140
/note="Midkine"
/id="PRO_0000024663"
SITE 100
/note="Required for high affinity binding to PTRZ1 by
interacting with the chondroitin sulfate chains of PTRZ1"
/evidence="ECO:0000269|PubMed:10212223"
DISULFID 34..58
/evidence="ECO:0000250"
DISULFID 42..67
/evidence="ECO:0000250"
DISULFID 49..71
/evidence="ECO:0000250"
DISULFID 81..113
/evidence="ECO:0000250"
DISULFID 91..123
/evidence="ECO:0000250"
MUTAGEN 100
/note="R->Q: Decreases affinity binding to PTPRZ1.
Decreases affinity binding to PTPRZ1; when associated with
Q-105 and Q-106. Decreases neuron migration. Decreases
neuron migration; when associated with Q-105 and Q-106."
/evidence="ECO:0000269|PubMed:10212223"
MUTAGEN 105
/note="K->Q: Does not affect binding with PTPRZ1. Does not
affect binding with PTPRZ1; when associated with Q-106.
Does not affect positive regulation of neuron migration."
/evidence="ECO:0000269|PubMed:10212223"
MUTAGEN 106
/note="K->Q: Does not affect binding with PTPRZ1. Does not
affect binding with PTPRZ1; when associated with Q-105.
Does not affect positive regulation of neuron migration."
/evidence="ECO:0000269|PubMed:10212223"
SEQUENCE 140 AA; 15434 MW; DAE31FEC94B29CF7 CRC64;
MQHRGFFLLA LLALLVVTSA VAKKKEKVKK GSECSEWTWG PCTPSSKDCG MGFREGTCGA
QTQRVHCKVP CNWKKEFGAD CKYKFESWGA CDGSTGTKAR QGTLKKARYN AQCQETIRVT
KPCTSKTKSK TKAKKGKGKD


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WP1648: Fatty acid metabolism
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Related Genes :
[Mdk Mk] Midkine (MK) (Retanoic acid-responsive protein) (Retinoic acid-induced differentiation factor)
[MDK MK1 NEGF2] Midkine (MK) (Amphiregulin-associated protein) (ARAP) (Midgestation and kidney protein) (Neurite outgrowth-promoting factor 2) (Neurite outgrowth-promoting protein)
[RARRES2 TIG2] Retinoic acid receptor responder protein 2 (Chemerin) (RAR-responsive protein TIG2) (Tazarotene-induced gene 2 protein)
[PLAAT4 RARRES3 RIG1 TIG3] Phospholipase A and acyltransferase 4 (EC 2.3.1.-) (EC 3.1.1.32) (EC 3.1.1.4) (HRAS-like suppressor 4) (HRSL4) (RAR-responsive protein TIG3) (Retinoic acid receptor responder protein 3) (Retinoid-inducible gene 1 protein) (Tazarotene-induced gene 3 protein)
[Gprc5a Rai3 Raig1] Retinoic acid-induced protein 3 (G-protein coupled receptor family C group 5 member A) (Retinoic acid-induced gene 1 protein) (RAIG-1)
[Stra6] Receptor for retinol uptake STRA6 (Retinoic acid-responsive protein) (Retinol-binding protein receptor STRA6) (Stimulated by retinoic acid gene 6 protein)
[Mdk] Midkine (MK)
[RXRA NR2B1] Retinoic acid receptor RXR-alpha (Nuclear receptor subfamily 2 group B member 1) (Retinoid X receptor alpha)
[Rxra Nr2b1] Retinoic acid receptor RXR-alpha (Nuclear receptor subfamily 2 group B member 1) (Retinoid X receptor alpha)
[RARA NR1B1] Retinoic acid receptor alpha (RAR-alpha) (Nuclear receptor subfamily 1 group B member 1)
[Rara Nr1b1] Retinoic acid receptor alpha (RAR-alpha) (Nuclear receptor subfamily 1 group B member 1)
[DDX58] Antiviral innate immune response receptor RIG-I (DEAD box protein 58) (Probable ATP-dependent RNA helicase DDX58) (EC 3.6.4.13) (RIG-I-like receptor 1) (RLR-1) (Retinoic acid-inducible gene 1 protein) (RIG-1) (Retinoic acid-inducible gene I protein) (RIG-I)
[DTL CDT2 CDW1 DCAF2 L2DTL RAMP] Denticleless protein homolog (DDB1- and CUL4-associated factor 2) (Lethal(2) denticleless protein homolog) (Retinoic acid-regulated nuclear matrix-associated protein)
[RXRG NR2B3] Retinoic acid receptor RXR-gamma (Nuclear receptor subfamily 2 group B member 3) (Retinoid X receptor gamma)
[MCL1 BCL2L3] Induced myeloid leukemia cell differentiation protein Mcl-1 (Bcl-2-like protein 3) (Bcl2-L-3) (Bcl-2-related protein EAT/mcl1) (mcl1/EAT)
[GPRC5B RAIG2] G-protein coupled receptor family C group 5 member B (A-69G12.1) (Retinoic acid-induced gene 2 protein) (RAIG-2)
[GPRC5C RAIG3 PSEC0087] G-protein coupled receptor family C group 5 member C (Retinoic acid-induced gene 3 protein) (RAIG-3)
[UBE2L6 UBCH8] Ubiquitin/ISG15-conjugating enzyme E2 L6 (EC 2.3.2.23) (E2 ubiquitin-conjugating enzyme L6) (Retinoic acid-induced gene B protein) (RIG-B) (UbcH8) (Ubiquitin carrier protein L6) (Ubiquitin-protein ligase L6)
[rxrga nr2b1 nr2b3a rxr rxra rxrg] Retinoic acid receptor RXR-gamma-A (Nuclear receptor subfamily 2 group B member 3-A) (Retinoic acid receptor RXR-alpha) (Retinoid X receptor alpha) (Retinoid X receptor gamma-A)
[TXNRD1 GRIM12 KDRF] Thioredoxin reductase 1, cytoplasmic (TR) (EC 1.8.1.9) (Gene associated with retinoic and interferon-induced mortality 12 protein) (GRIM-12) (Gene associated with retinoic and IFN-induced mortality 12 protein) (KM-102-derived reductase-like factor) (Thioredoxin reductase TR1)
[rxrbb nr2b2b rxrd] Retinoic acid receptor RXR-beta-B (Nuclear receptor subfamily 2 group B member 2-B) (Retinoic acid receptor RXR-delta) (Retinoid X receptor beta-B) (Retinoid X receptor delta)
[BZIP46 ABF2 ABF3 ABL1 AREB8 Os06g0211200 LOC_Os06g10880 P0021C04.25 P0701E03.2] bZIP transcription factor 46 (OsBZIP46) (AREB/ABF-family transcription factor 8) (OsAREB8) (Abscisic acid responsive elements-binding factor 2) (ABRE-binding factor 2) (OsABF2) (Abscisic acid responsive elements-binding factor 3) (ABRE-binding factor 3) (OsABF3) (Protein ABI5-LIKE 1)
[Rxra Nr2b1] Retinoic acid receptor RXR-alpha (Nuclear receptor subfamily 2 group B member 1) (Retinoid X receptor alpha)
[Rxrb Nr2b2] Retinoic acid receptor RXR-beta (MHC class I regulatory element-binding protein H-2RIIBP) (Nuclear receptor subfamily 2 group B member 2) (Retinoid X receptor beta)
[NAV2 HELAD1 KIAA1419 POMFIL2 RAINB1 STEERIN2] Neuron navigator 2 (EC 3.6.4.12) (Helicase APC down-regulated 1) (Pore membrane and/or filament-interacting-like protein 2) (Retinoic acid inducible in neuroblastoma 1) (Steerin-2) (Unc-53 homolog 2) (unc53H2)
[RXRB NR2B2] Retinoic acid receptor RXR-beta (Nuclear receptor subfamily 2 group B member 2) (Retinoid X receptor beta)
[Hoxa1 Era-1 Hox-1.6 Hoxa-1] Homeobox protein Hox-A1 (Early retinoic acid 1) (Homeobox protein Hox-1.6) (Homeoboxless protein ERA-1-399) (Homeotic protein ERA-1-993)
[Rxrg Nr2b3] Retinoic acid receptor RXR-gamma (Nuclear receptor subfamily 2 group B member 3) (Retinoid X receptor gamma)
[rarab nr1b1b rara2b] Retinoic acid receptor alpha-B (RAR-alpha-B) (Nuclear receptor subfamily 1 group B member 1-B) (Retinoic acid receptor alpha-2.B) (RAR-alpha-2.B)
[Rarres2] Retinoic acid receptor responder protein 2 (Chemerin)

Bibliography :