Reviewed, UniProtKB/Swiss-Prot Q61039 (HAND2_MOUSE)

Names and origin

Protein names

Recommended name:
    Heart- and neural crest derivatives-expressed protein 2
Alternative name(s):
    Deciduum, heart, autonomic nervous system and neural crest derivatives-expressed protein 2
      Short name=dHAND
    Helix-loop-helix transcription factor expressed in embryo and deciduum
    Thing-2

Gene names

Name:	Hand2
Synonyms:	Dhand, Hed, Thing2

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	217 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Essential for cardiac morphogenesis, particularly for the formation of the right ventricle and of the aortic arch arteries. Required for vascular development and regulation of angiogenesis, possibly through a VEGF signaling pathway. Plays also an important role in limb development, particularly in the establishment of anterior-posterior polarization, acting as an upstream regulator of sonic hedgehog (SHH) induction in the limb bud. Is involved in the development of branchial arches, which give rise to unique structures in the head and neck. Binds DNA on E-box consensus sequence 5'-CANNTG-3'. Ref.4 Ref.5 Ref.7 Ref.8
Subunit structure	Efficient DNA binding requires dimerization with another bHLH protein. Forms homodimers and heterodimers with TCF3 gene products E12 and E47, HAND1 and HEY1, HEY2 and HEYL (hairy-related transcription factors). Ref.6
Subcellular location	Nucleus By similarity.
Tissue specificity	Heart and aorta.
Developmental stage	High extraembryonic expression is detected at 7.5 dpc in the maternally derived deciduum. Also detected along the yolk sac vessels during the process of remodeling at 9.5-10.0 dpc. Within the embryo, detected at 7.5 dpc in the lateral mesoderm including the precardiac mesoderm. On day 8.5 pc expressed throughout the straight heart tube. In the caudal region of the embryo, expressed in the lateral mesoderm at the level of separation of the somatic and splanchnic mesoderm. On day 9.5 pc expressed throughout the developing cardiovascular region, most abundant in the outflow tract and in the first and second aortic arch arteries, and in pharyngeal arches. As the heart loops, the expression becomes restricted to the conotruncus and future right ventricle (endocardium and myocardium). At 10.5 dpc, highly expressed in the branchial arches, as well as in the truncus arteriosus, aortic sac, and the vascular mesenchyme between the third and fourth aortic arch arteries, which later gives rise to vascular smooth muscle cells and to the mesenchyme of the pharyngeal arch. At 13.5 dpc, barely detectable in the heart, but apparent in the neural crest-derived sympathetic trunk and adrenal medulla, a pattern similar to that of HAND1. In the developing limbs, expression is detected in the posterior mesoderm of the buds at 9.5 dpc. It is then progressively down-regulated at the anterior of the limb buds so that a gradient expression along the anterior-posterior axis of the bud is established with higher expression at the posterior border. At later stages of limb development, expression is restricted to the posterior border of the zeugopod and to the posterior autopod. In the autopod, dynamic expression of HAND2 affects the interdigital regions, the lateral borders of the digits and eventually the developing ventral tendons. After 16 dpc, expression decreases throughout the embryo. Ref.4 Ref.7 Ref.8
Sequence similarities	Contains 1 basic helix-loop-helix (bHLH) domain.
Sequence caution	The sequence AAA86274.1 differs from that shown. Reason: Frameshift at position 183. The sequence AAC52338.1 differs from that shown. Reason: Frameshift at positions 20 and 43.

Ontologies

Keywords
Biological process	Angiogenesis Differentiation Transcription Transcription regulation
Cellular component	Nucleus
Ligand	DNA-binding
Molecular function	Developmental protein
Gene Ontology (GO)
Biological process	adult heart development Ref.4 Inferred from mutant phenotype. Source: MGI angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW apoptosis Inferred from mutant phenotype. Source: MGI heart looping Ref.4 Inferred from mutant phenotype. Source: MGI in utero embryonic development Ref.4 Inferred from mutant phenotype. Source: MGI neural crest cell development Ref.5 Inferred from mutant phenotype. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: MGI transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	transcription factor complex Inferred from direct assay. Source: MGI
Molecular function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW identical protein binding Ref.6 Inferred from physical interaction. Source: IntAct protein heterodimerization activity Inferred from physical interaction. Source: MGI transcription regulator activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		1	EBI-81388,EBI-81388
Hand1	Q64279	2	EBI-81388,EBI-81361
Hey1	Q9WV93	1	EBI-81388,EBI-81432
Hey2	Q9QUS4	1	EBI-81388,EBI-81414
Heyl	Q9DBX7	1	EBI-81388,EBI-81443
Mcf2	Q99N72	2	EBI-81388,EBI-641874
Tcf3	P15806	1	EBI-81388,EBI-81370

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 217	217	Heart- and neural crest derivatives-expressed protein 2		PRO_0000127192
Regions
	Domain	112 – 155	44	Helix-loop-helix motif
	DNA binding	99 – 111	13	Basic motif
	Compositional bias	21 – 32	12	Poly-Ala
Experimental info
	Sequence conflict	92 – 93	2	LG → TA in AAA86274. Ref.3
	Sequence conflict	156	1	A → P in AAC52338. Ref.1
	Sequence conflict	166	1	A → G in AAA86274. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q61039-1 [UniParc]. Last modified May 10, 2004. Version 3. Checksum: 528F541BB2173F1E	FASTA	217	23,666
	10 20 30 40 50 60 MSLVGGFPHH PVVHHEGYPF AAAAAAAAAA AASRCSHEEN PYFHGWLIGH PEMSPPDYSM 70 80 90 100 110 120 ALSYSPEYAS GAAGLDHSHY GGVPPGAGPP GLGGPRPVKR RGTANRKERR RTQSINSAFA 130 140 150 160 170 180 ELRECIPNVP ADTKLSKIKT LRLATSYIAY LMDLLAKDDQ NGEAEAFKAE IKKTDVKEEK 190 200 210 RKKELNEILK STVSSNDKKT KGRTGWPQHV WALELKQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A subclass of bHLH proteins required for cardiac morphogenesis." Srivastava D., Cserjesi P., Olson E.N. Science 270:1995-1998(1995) [PubMed: 8533092] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Embryo.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J.
[3]	"Hxt encodes a basic helix-loop-helix transcription factor that regulates trophoblast cell development." Cross J.C., Flannery M.L., Blanar M.A., Steingrimsson E., Jenkins N.A., Copeland N.G., Rutter W.J., Werb Z. Development 121:2513-2523(1995) [PubMed: 7671815] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 92-203. Strain: 129/Sv. Tissue: Embryoid bodies.
[4]	"Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND." Srivastava D., Thomas T., Lin Q., Kirby M.L., Brown D., Olson E.N. Nat. Genet. 16:154-160(1997) [PubMed: 9171826] [Abstract] Cited for: FUNCTION, DEVELOPMENTAL STAGE.
[5]	"A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme." Thomas T., Kurihara H., Yamagishi H., Kurihara Y., Yazaki Y., Olson E.N., Srivastava D. Development 125:3005-3014(1998) [PubMed: 9671575] [Abstract] Cited for: FUNCTION.
[6]	"The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function." Firulli B.A., Hadzic D.B., McDaid J.R., Firulli A.B. J. Biol. Chem. 275:33567-33573(2000) [PubMed: 10924525] [Abstract] Cited for: SUBUNIT.
[7]	"The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development." Charite J., McFadden D.G., Olson E.N. Development 127:2461-2470(2000) [PubMed: 10804186] [Abstract] Cited for: FUNCTION, DEVELOPMENTAL STAGE.
[8]	"Role of dHAND in the anterior-posterior polarization of the limb bud: implications for the Sonic hedgehog pathway." Fernandez-Teran M., Piedra M.E., Kathiriya I.S., Srivastava D., Rodriguez-Rey J.C., Ros M.A. Development 127:2133-2142(2000) [PubMed: 10769237] [Abstract] Cited for: FUNCTION, DEVELOPMENTAL STAGE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	U40039 Genomic DNA. Translation: AAC52338.1. Frameshift. AK035160 mRNA. Translation: BAC28965.1. U43715 mRNA. Translation: AAA86274.1. Frameshift.
IPI	IPI00116995.
RefSeq	NP_034532.3.
UniGene	Mm.430844
3D structure databases
HSSP	HSSP built from PDB template 1AN4 based on UniProtKB P22415.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q61039. 7 interactions.
Genome annotation databases
Ensembl	ENSMUSG00000038193. Mus musculus. [Contig view]
GeneID	15111.
KEGG	mmu:15111.
Organism-specific databases
MGI	MGI:103580. Hand2.
Phylogenomic databases
HOGENOM	Q61039.
HOVERGEN	Q61039.
OMA	Q61039. LISHPEM.
Gene expression databases
ArrayExpress	Q61039.
Bgee	Q61039.
GermOnline	ENSMUSG00000038193. Mus musculus.
Family and domain databases
InterPro	IPR001092. HLH_basic. IPR011598. HLH_DNA_bd. [Graphical view]
Gene3D	G3DSA:4.10.280.10. HLH_DNA_bd. 1 hit.
Pfam	PF00010. HLH. 1 hit. [Graphical view]
SMART	SM00353. HLH. 1 hit. [Graphical view]
PROSITE	PS50888. HLH. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	287514.
SOURCE	Search...

Entry information

Entry name

HAND2_MOUSE

Accession

Primary (citable) accession number: Q61039
Secondary accession number(s): Q61100

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	May 10, 2004
Last modified:	June 16, 2009
This is version 92 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)