P21741 (MK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Midkine
Short name=MK

Alternative name(s):
Amphiregulin-associated protein
Short name=ARAP
Midgestation and kidney protein
Neurite outgrowth-promoting factor 2
Neurite outgrowth-promoting protein

Gene names

Name:	MDK
Synonyms:	MK1, NEGF2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	143 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Developmentally regulated, secreted growth factor homologous to pleiotrophin (PTN), which has heparin binding activity. Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation. Involved in neointima formation after arterial injury, possibly by mediating leukocyte recruitment. Also involved in early fetal adrenal gland development By similarity. Ref.2 Ref.9
Subunit structure	Homodimer. Interacts with ALK. Ref.9 Ref.10
Subcellular location	Secreted.
Induction	By heparin and retinoic acid. Ref.2 Ref.7
Sequence similarities	Belongs to the pleiotrophin family.

Ontologies

Keywords
Biological process	Differentiation
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Ligand	Heparin-binding
Molecular function	Developmental protein Growth factor Mitogen
PTM	Disulfide bond
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	adrenal gland development Inferred from sequence or structural similarity. Source: UniProtKB cell differentiation Non-traceable author statement Ref.3. Source: UniProtKB positive regulation of cell division Inferred from electronic annotation. Source: UniProtKB-KW response to wounding Inferred from sequence or structural similarity. Source: UniProtKB signal transduction Non-traceable author statement. Source: ProtInc
Cellular component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	growth factor activity Non-traceable author statement Ref.3. Source: UniProtKB heparin binding Inferred from direct assay Ref.10. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 20

20

Ref.6 Ref.7 Ref.8

Chain

21 – 143

123

Midkine

PRO_0000024662

Amino acid modifications

Disulfide bond

37 ↔ 61

Disulfide bond

45 ↔ 70

Disulfide bond

52 ↔ 74

Disulfide bond

84 ↔ 116

Disulfide bond

94 ↔ 126

Natural variations

Natural variant

21 – 22

2

Missing in 35% of the chains.

VAR_006353

Secondary structure

1

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143

Helix Strand Turn

Details...

Beta strand

29 – 31

3

Beta strand

38 – 43

6

Beta strand

48 – 54

7

Beta strand

57 – 63

7

Beta strand

66 – 68

3

Beta strand

76 – 79

4

Beta strand

96 – 100

5

Beta strand

111 – 115

5

Beta strand

118 – 120

3

Sequences

	Sequence		Length	Mass (Da)
	P21741 [UniParc]. Last modified May 1, 1991. Version 1. Checksum: 414A627FF39953C3	FASTA	143	15,585
	10 20 30 40 50 60 MQHRGFLLLT LLALLALTSA VAKKKDKVKK GGPGSECAEW AWGPCTPSSK DCGVGFREGT 70 80 90 100 110 120 CGAQTQRIRC RVPCNWKKEF GADCKYKFEN WGACDGGTGT KVRQGTLKKA RYNAQCQETI 130 140 RVTKPCTPKT KAKAKAKKGK GKD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A new family of heparin-binding factors: strong conservation of midkine (MK) sequences between the human and the mouse." Tsutsui J., Uehara K., Kadomatsu K., Matsubara S., Muramatsu T. Biochem. Biophys. Res. Commun. 176:792-797(1991) [PubMed: 2025291] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Kidney.
[2]	"Cloning, characterization and developmental regulation of two members of a novel human gene family of neurite outgrowth-promoting proteins." Kretschmer P.J., Fairhurst J.L., Decker M.M., Chan C.P., Gluzman Y., Boehlen P., Kovesdi I. Growth Factors 5:99-114(1991) [PubMed: 1768439] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INDUCTION. Tissue: Fetal brain.
[3]	"Genomic structure of human midkine (MK), a retinoic acid-responsive growth/differentiation factor." Uehara K., Matsubara S., Kadomatsu K., Tsutsui J., Muramatsu T. J. Biochem. 111:563-567(1992) [PubMed: 1639750] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Structure of the gene coding for the human retinoic acid-inducible factor, MK." Fairhurst J.L., Kretschmer P.J., Gluzman Y., Boehlen P., Kovesdi I. DNA Cell Biol. 12:139-147(1993) [PubMed: 8471163] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Fetal brain.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Uterus.
[6]	"Amphiregulin-associated protein: complete amino acid sequence of a protein produced by the 12-0-tetradecanoylphorbol-13-acetate-treated human breast adenocarcinoma cell line MCF-7." Shoyab M., McDonald V.L., Dick K., Modrell B., Malik N., Plowman G.D. Biochem. Biophys. Res. Commun. 179:572-578(1991) [PubMed: 1883381] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-143.
[7]	"Identification of novel heparin-releasable proteins, as well as the cytokines midkine and pleiotrophin, in human postheparin plasma." Novotny W.F., Maffi T., Mehta R.L., Milner P.G. Arterioscler. Thromb. 13:1798-1805(1993) [PubMed: 8241100] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-35, INDUCTION. Tissue: Plasma.
[8]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-35.
[9]	"Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types." Stoica G.E., Kuo A., Powers C., Bowden E.T., Sale E.B., Riegel A.T., Wellstein A. J. Biol. Chem. 277:35990-35998(2002) [PubMed: 12122009] [Abstract] Cited for: INTERACTION WITH ALK, FUNCTION.
[10]	"Solution structure of midkine, a new heparin-binding growth factor." Iwasaki W., Nagata K., Hatanaka H., Inui T., Kimura T., Muramatsu T., Yoshida K., Tasumi M., Inagaki F. EMBO J. 16:6936-6946(1997) [PubMed: 9384573] [Abstract] Cited for: STRUCTURE BY NMR OF 23-81 AND 84-126, HOMODIMERIZATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M69148 mRNA. Translation: AAA58478.1.
X55110 mRNA. Translation: CAA38908.1.
D10604 Genomic DNA. Translation: BAA01457.1.
M94250 Genomic DNA. Translation: AAA59850.1.
BC011704 mRNA. Translation: AAH11704.1.

IPI

IPI00010333.

PIR

JH0385.

RefSeq

NP_001012333.1. NM_001012333.1.
NP_001012334.1. NM_001012334.1.
NP_002382.1. NM_002391.3.

UniGene

Hs.82045.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1MKC	NMR	-	A	84-126	[»]
1MKN	NMR	-	A	23-81	[»]

ProteinModelPortal

P21741.

SMR

P21741. Positions 31-81, 84-126.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-5789N.

IntAct

P21741. 2 interactions.

MINT

MINT-1385688.

STRING

P21741.

PTM databases

PhosphoSite

P21741.

Polymorphism databases

DMDM

127116.

Proteomic databases

PRIDE

P21741.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000359803; ENSP00000352852; ENSG00000110492.
ENST00000395565; ENSP00000378932; ENSG00000110492.
ENST00000395566; ENSP00000378933; ENSG00000110492.
ENST00000405308; ENSP00000385451; ENSG00000110492.
ENST00000405994; ENSP00000384824; ENSG00000110492.
ENST00000407067; ENSP00000384034; ENSG00000110492.

GeneID

4192.

KEGG

hsa:4192.

UCSC

uc001nco.1. human.

Organism-specific databases

CTD

4192.

GeneCards

GC11P046359.

H-InvDB

HIX0009601.

HGNC

HGNC:6972. MDK.

HPA

CAB010055.

MIM

162096. gene.

neXtProt

NX_P21741.

PharmGKB

PA30717.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG20333.

GeneTree

ENSGT00500000045558.

HOVERGEN

HBG008317.

OMA

GFREGTC.

OrthoDB

EOG4CRM1M.

PhylomeDB

P21741.

Enzyme and pathway databases

Pathway_Interaction_DB

glypican_2pathway. Glypican 2 network.
syndecan_4_pathway. Syndecan-4-mediated signaling events.

Gene expression databases

ArrayExpress

P21741.

Bgee

P21741.

CleanEx

HS_MDK.

Genevestigator

P21741.

GermOnline

ENSG00000110492. Homo sapiens.

Family and domain databases

InterPro

IPR000762. Midkine_heparin-bd_GF.
IPR020090. Midkine_heparin-bd_GF_C.
IPR020092. Midkine_heparin-bd_GF_CS.
IPR020091. Midkine_heparin-bd_GF_diS.
IPR020089. Midkine_heparin-bd_GF_N.
[Graphical view]

Gene3D

G3DSA:2.20.60.10. PTN_MK_hepar_bd. 1 hit.
G3DSA:2.30.90.10. PTN_MK_hepar_bd. 1 hit.

KO

K06828.

PANTHER

PTHR13850. PTN_MK_hepar_bd. 1 hit.

Pfam

PF01091. PTN_MK_C. 1 hit.
PF05196. PTN_MK_N. 1 hit.
[Graphical view]

PRINTS

PR00269. PTNMIDKINE.

ProDom

PD005592. PTN_MK_hepar_bd. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00193. PTN. 1 hit.
[Graphical view]

SUPFAM

SSF57288. PTN_MK_hepar_bd. 2 hits.

PROSITE

PS00619. PTN_MK_1. 1 hit.
PS00620. PTN_MK_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

16518.

SOURCE

Search...

Entry information

Entry name

MK_HUMAN

Accession

Primary (citable) accession number: P21741
Secondary accession number(s): Q9UCC7

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1991
Last sequence update:	May 1, 1991
Last modified:	January 25, 2012
This is version 110 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.