P35548 (MSX2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Homeobox protein MSX-2

Alternative name(s):
Homeobox protein Hox-8

Gene names

Name:	MSX2
Synonyms:	HOX8

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	267 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Acts as a transcriptional regulator in bone development. Represses the ALPL promoter activity and antogonizes the stimulatory effect of DLX5 on ALPL expression during osteoblast differentiation. Probable morphogenetic role. May play a role in limb-pattern formation. In osteoblasts, suppresses transcription driven by the osteocalcin FGF response element (OCFRE). Binds to the homeodomain-response element of the ALPL promoter. Ref.11
Subunit structure	Interacts with MINT By similarity. Interacts with XRCC6 (Ku70) and XRCC5 (Ku80). Ref.11
Subcellular location	Nucleus.
Involvement in disease	Parietal foramina 1 (PFM1) [MIM:168500]: Autosomal dominant disease characterized by oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.13 Ref.14 Parietal foramina with cleidocranial dysplasia (PFMCCD) [MIM:168550]: Combines skull defects in the form of enlarged parietal foramina and deficient ossification of the clavicles. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12 Craniosynostosis 2 (CRS2) [MIM:604757]: An autosomal dominant disorder characterized by the premature fusion of calvarial sutures. The craniosynostosis phenotype is either fronto-orbital recession, or frontal bossing, or turribrachycephaly, or cloverleaf skull. Associated features include severe headache, high incidence of visual problems (myopia or hyperopia), and short first metatarsals. Intelligence is normal. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.2
Sequence similarities	Belongs to the Msh homeobox family. Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
Biological process	Osteogenesis Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Disease	Craniosynostosis Disease mutation
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Developmental protein Repressor
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	BMP signaling pathway involved in heart development Inferred from electronic annotation. Source: Compara anagen Inferred from electronic annotation. Source: Compara anterior/posterior pattern specification Inferred from electronic annotation. Source: Compara bone trabecula formation Inferred from electronic annotation. Source: Compara branching involved in mammary gland duct morphogenesis Inferred from electronic annotation. Source: Compara cellular response to estradiol stimulus Inferred from electronic annotation. Source: Compara cellular response to growth factor stimulus Inferred from electronic annotation. Source: Compara chondrocyte development Inferred from electronic annotation. Source: Compara cranial suture morphogenesis Traceable author statement PubMed 8968743. Source: BHF-UCL embryonic forelimb morphogenesis Inferred from electronic annotation. Source: Compara embryonic hindlimb morphogenesis Inferred from electronic annotation. Source: Compara embryonic nail plate morphogenesis Inferred from electronic annotation. Source: Compara enamel mineralization Inferred from electronic annotation. Source: Compara endochondral bone growth Inferred from electronic annotation. Source: Compara epithelial to mesenchymal transition involved in endocardial cushion formation Inferred from electronic annotation. Source: Compara frontal suture morphogenesis Inferred from electronic annotation. Source: Compara negative regulation of CREB transcription factor activity Inferred from electronic annotation. Source: Compara negative regulation of apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of fat cell differentiation Inferred from electronic annotation. Source: Compara negative regulation of keratinocyte differentiation Inferred from electronic annotation. Source: Compara negative regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of transcription regulatory region DNA binding Inferred from sequence or structural similarity. Source: BHF-UCL osteoblast development Inferred from electronic annotation. Source: Compara osteoblast differentiation Inferred from sequence or structural similarity. Source: UniProtKB outflow tract septum morphogenesis Inferred from electronic annotation. Source: Compara positive regulation of BMP signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of apoptotic process Inferred from electronic annotation. Source: Compara positive regulation of catagen Inferred from electronic annotation. Source: Compara positive regulation of osteoblast differentiation Inferred from electronic annotation. Source: Compara signal transduction involved in regulation of gene expression Inferred from electronic annotation. Source: Compara stem cell differentiation Inferred from electronic annotation. Source: Compara wound healing, spreading of epidermal cells Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from direct assay. Source: HPA nucleus Inferred from direct assay. Source: HPA transcription factor complex Inferred from electronic annotation. Source: Compara
Molecular_function	RNA polymerase II core promoter proximal region sequence-specific DNA binding Inferred from electronic annotation. Source: Compara RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara sequence-specific DNA binding Inferred from direct assay PubMed 9073066. Source: MGI transcription cofactor activity Inferred from sequence or structural similarity. Source: BHF-UCL transcription regulatory region DNA binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 267	267	Homeobox protein MSX-2		PRO_0000049099
Regions
	DNA binding	142 – 201	60	Homeobox
Natural variations
	Natural variant	129	1	M → T. Ref.1 Ref.2 Ref.3 Ref.5 Ref.7 Ref.8 Ref.9 Ref.14 Corresponds to variant rs4242182 [ dbSNP | Ensembl ].		VAR_010898
	Natural variant	148	1	P → H in CRS2; gain of function. Ref.2		VAR_003755
	Natural variant	154	1	L → P in PFM1. Ref.13		VAR_010786
	Natural variant	159 – 160	2	Missing in PFM1; loss of function.		VAR_010200
	Natural variant	172	1	R → H in PFM1; loss of function. Ref.13 Ref.14		VAR_010201
Experimental info
	Mutagenesis	147	1	T → A: Does not bind DNA but still suppresses OCFRE activation. Ref.11
	Sequence conflict	28	1	P → L in CAA49156. Ref.1
	Sequence conflict	32	1	E → A in CAA49156. Ref.1
	Sequence conflict	62 – 65	4	ASPL → SPAV in CAA49156. Ref.1
	Sequence conflict	67	1	A → P in CAA49156. Ref.1
	Sequence conflict	69	1	S → G in CAA49156. Ref.1
	Sequence conflict	75	1	T → H in CAA49156. Ref.1
	Sequence conflict	85	1	G → R in CAA49156. Ref.1
	Sequence conflict	107	1	E → G in CAA49156. Ref.1
	Sequence conflict	194	1	R → S in CAA49156. Ref.1
	Sequence conflict	237	1	G → A in CAA49156. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P35548 [UniParc]. Last modified November 2, 2010. Version 3. Checksum: 5B61B75F4A7C4AFD	FASTA	267	28,897
	10 20 30 40 50 60 MASPSKGNDL FSPDEEGPAV VAGPGPGPGG AEGAAEERRV KVSSLPFSVE ALMSDKKPPK 70 80 90 100 110 120 EASPLPAESA SAGATLRPLL LSGHGAREAH SPGPLVKPFE TASVKSENSE DGAAWMQEPG 130 140 150 160 170 180 RYSPPPRHMS PTTCTLRKHK TNRKPRTPFT TSQLLALERK FRQKQYLSIA ERAEFSSSLN 190 200 210 220 230 240 LTETQVKIWF QNRRAKAKRL QEAELEKLKM AAKPMLPSSF SLPFPISSPL QAASIYGASY 250 260 PFHRPVLPIP PVGLYATPVG YGMYHLS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Expression of a human homeobox-containing gene is regulated by 1,25(OH)2D3 in bone cells." Hodgkinson J.E., Davidson C.L., Beresford J., Sharpe P.T. Biochim. Biophys. Acta 1174:11-16(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT THR-129. Tissue: Osteoblast.
[2]	"A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis." Jabs E.W., Ma L., Li X., Mueller U., Sparkes R.S., Luo W., Jackson C.E., Warman M.L., Mulliken J.B., Snead M., Haworth I., Maxson R.E. Cell 75:443-450(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS THR-129 AND CRS2 HIS-148.
[3]	"Molecular cloning and expression of homeobox-containing genes during hard tissue development." Iimura T. Kokubyo Gakkai Zasshi 61:590-604(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT THR-129.
[4]	"Characterization of two length cDNA for human MSX-2 from dental pulp-derived cells." Iimura T., Takeda K., Goseki M., Maruoka Y., Sasaki S., Oida S. DNA Seq. 8:87-92(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Tooth.
[5]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT THR-129.
[6]	"The DNA sequence and comparative analysis of human chromosome 5." Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M. Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT THR-129.
[8]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT THR-129. Tissue: Pancreas.
[9]	"Over-expression of HOX-8, the human homologue of the mouse Hox-8 homeobox gene, in human tumors." Suzuki M., Tanaka M., Iwase T., Naito Y., Sugimura H., Kino I. Biochem. Biophys. Res. Commun. 194:187-193(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 96-267, VARIANT THR-129. Tissue: Ovary tumor.
[10]	"Identification of homeobox genes expressed in human haemopoietic progenitor cells." Moretti P., Simmons P., Thomas P., Haylock D., Rathjen P., Vadas M., D'Andrea R. Gene 144:213-219(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 150-188. Tissue: Bone marrow.
[11]	"Regulation of osteocalcin gene expression by a novel Ku antigen transcription factor complex." Willis D.M., Loewy A.P., Charlton-Kachigian N., Shao J.-S., Ornitz D.M., Towler D.A. J. Biol. Chem. 277:37280-37291(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH XRCC6 AND XRCC5, MUTAGENESIS OF THR-147. Tissue: Osteoblast.
[12]	"Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2." Garcia-Minaur S., Mavrogiannis L.A., Rannan-Eliya S.V., Hendry M.A., Liston W.A., Porteous M.E.M., Wilkie A.O.M. Eur. J. Hum. Genet. 11:892-895(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN PFMCCD.
[13]	"Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna." Wuyts W., Reardon W., Preis S., Homfray T., Rasore-Quartino A., Christians H., Willems P.J., Van Hul W. Hum. Mol. Genet. 9:1251-1255(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS PFM1 PRO-154 AND HIS-172.
[14]	"Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification." Wilkie A.O.M., Tang Z., Elanko N., Walsh S., Twigg S.R.F., Hurst J.A., Wall S.A., Chrzanowska K.H., Maxson R.E. Jr. Nat. Genet. 24:387-390(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS PFM1 159-ARG-LYS-160 DEL AND HIS-172, VARIANT THR-129.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	X69295 mRNA. Translation: CAA49156.1. L22499, L22498 Genomic DNA. Translation: AAB42178.1. S75308 Genomic DNA. Translation: AAD14169.1. S75361 mRNA. Translation: AAB33867.1. D31771 mRNA. Translation: BAA06549.1. D89377 mRNA. Translation: BAA13949.1. BT009814 mRNA. Translation: AAP88816.1. AC117531 Genomic DNA. No translation available. CH471062 Genomic DNA. Translation: EAW61381.1. CH471062 Genomic DNA. Translation: EAW61382.1. BC015509 mRNA. Translation: AAH15509.1. D14970 mRNA. Translation: BAA03611.1.
IPI	IPI00292686.
PIR	A49068.
RefSeq	NP_002440.2. NM_002449.4.
UniGene	Hs.89404.
3D structure databases
ProteinModelPortal	P35548.
SMR	P35548. Positions 143-200.
ModBase	Search...
Protein-protein interaction databases
IntAct	P35548. 1 interaction.
STRING	9606.ENSP00000239243.
PTM databases
PhosphoSite	P35548.
Polymorphism databases
DMDM	311033429.
Proteomic databases
PaxDb	P35548.
PRIDE	P35548.
Protocols and materials databases
DNASU	4488.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000239243; ENSP00000239243; ENSG00000120149.
GeneID	4488.
KEGG	hsa:4488.
UCSC	uc003mcy.3. human.
Organism-specific databases
CTD	4488.
GeneCards	GC05P174084.
H-InvDB	HIX0005431.
HGNC	HGNC:7392. MSX2.
HPA	HPA005652.
MIM	123101. gene. 168500. phenotype. 168550. phenotype. 604757. phenotype.
neXtProt	NX_P35548.
Orphanet	1541. Craniosynostosis, Boston type. 60015. Parietal foramina. 251290. Parietal foramina with cleidocranial dysplasia.
PharmGKB	PA31197.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG298790.
HOGENOM	HOG000231922.
HOVERGEN	HBG005205.
InParanoid	P35548.
KO	K09341.
OMA	PKEASPR.
OrthoDB	EOG4HQDK0.
PhylomeDB	P35548.
Gene expression databases
ArrayExpress	P35548.
Bgee	P35548.
CleanEx	HS_MSX2.
Genevestigator	P35548.
GermOnline	ENSG00000120149. Homo sapiens.
Family and domain databases
Gene3D	1.10.10.60. 1 hit.
InterPro	IPR017970. Homeobox_CS. IPR020479. Homeobox_metazoa. IPR001356. Homeodomain. IPR009057. Homeodomain-like. [Graphical view]
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
PRINTS	PR00024. HOMEOBOX.
SMART	SM00389. HOX. 1 hit. [Graphical view]
SUPFAM	SSF46689. Homeodomain_like. 1 hit.
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	4488.
NextBio	17363.
SOURCE	Search...

Entry information

Entry name

MSX2_HUMAN

Accession

Primary (citable) accession number: P35548
Secondary accession number(s): D3DQN1, Q53XM4, Q9UD60

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	November 2, 2010
Last modified:	May 1, 2013
This is version 135 of the entry and version 3 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.