ZEB2

Zinc finger E-box binding homeobox 2
PDB rendering based on 2da7.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2DA7​
Identifiers
Symbols	ZEB2 ; HSPC082; SIP-1; SIP1; SMADIP1; ZFHX1B
External IDs	OMIM: 605802 MGI: 1344407 HomoloGene: 8868 GeneCards: ZEB2 Gene
Gene ontology Molecular function • DNA binding • phosphatase regulator activity • metal ion binding Cellular component • nucleus Biological process • negative regulation of transcription from RNA polymerase II promoter • transcription, DNA-templated • nervous system development • positive regulation of melanocyte differentiation • positive regulation of transcription from RNA polymerase II promoter • positive regulation of melanin biosynthetic process • developmental pigmentation • regulation of catalytic activity • melanocyte migration • regulation of melanosome organization Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	9839	24136
Ensembl	ENSG00000169554	ENSMUSG00000026872
UniProt	O60315	Q9R0G7
RefSeq (mRNA)	NM_001171653	NM_001289521
RefSeq (protein)	NP_001165124	NP_001276450
Location (UCSC)	Chr 2: 144.38 – 144.52 Mb	Chr 2: 44.98 – 45.12 Mb
PubMed search

Zinc finger E-box-binding homeobox 2 is a protein that in humans is encoded by the ZEB2 gene.^[1] The ZEB2 protein is a transcription factor that plays a role in the transforming growth factor β (TGFβ) signaling pathways that are essential during early fetal development.^[2]

Function

The SMADIP1 gene (also known as SIP1) is a member of the delta-EF1 (TCF8)/Zfh1 family of 2-handed zinc finger/homeodomain proteins. SMADIP1 interacts with receptor-mediated, activated full-length SMADs.^[1]

The activation of TGFβ receptors brings about the phosphorylation of intracellular effector molecules, R-SMADs. ZEB2 is an R-SMAD-binding protein and acts as a transcriptional corepressor.

ZEB2 transcripts are found in tissues differentiated from the neural crest such as the cranial nerve ganglia, dorsal root ganglia, sympathetic ganglionic chains, and the enteric nervous system. ZEB2 is also found in tissues that are not derived from the neural crest, including the wall of the digestive tract, kidneys, and skeletal muscles.

Clinical significance

Mutations in the ZEB2 gene are associated with the Mowat-Wilson syndrome. This disease exhibits mutations and even complete deletions of the ZEB2 gene. Mutations of the gene can cause the gene to produce nonfunctional ZEB2 proteins or inactivate the function gene as a whole. These deficits of ZEB2 protein interferes with the development of many organs. Many of the symptoms can be explained by the irregular development of the structures from the neural crest.^[3]

Hirschsprug's disease also has many symptoms that can be explained by lack of ZEB2 during development of the digestive tract nerves. This disease causes severe constipation and enlargement of the colon.^[4]

References

1. "Entrez Gene: ZEB2 zinc finger E-box binding homeobox 2".
2. Bassez G, Camand OJ, Cacheux V, Kobetz A, Dastot-Le Moal F, Marchant D, Catala M, Abitbol M, Goossens M (March 2004). "Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the "Mowat-Wilson" syndrome". Neurobiology of Disease 15 (2): 240–50. doi:10.1016/j.nbd.2003.10.004. PMID 15006694.
3. Dastot-Le Moal F, Wilson M, Mowat D, Collot N, Niel F, Goossens M (April 2007). "ZFHX1B mutations in patients with Mowat-Wilson syndrome". Human Mutation 28 (4): 313–21. doi:10.1002/humu.20452. PMID 17203459.
4. Saunders CJ, Zhao W, Ardinger HH (November 2009). "Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics". American Journal of Medical Genetics. Part A 149A (11): 2527–31. doi:10.1002/ajmg.a.33067. PMID 19842203.

Further reading

• Mowat DR, Wilson MJ, Goossens M (May 2003). "Mowat-Wilson syndrome". Journal of Medical Genetics 40 (5): 305–10. doi:10.1136/jmg.40.5.305. PMC 1735450. PMID 12746390.
• Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (February 1998). "Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research 5 (1): 31–9. doi:10.1093/dnares/5.1.31. PMID 9628581.
• Ueki N, Oda T, Kondo M, Yano K, Noguchi T, Muramatsu M (December 1998). "Selection system for genes encoding nuclear-targeted proteins". Nature Biotechnology 16 (13): 1338–42. doi:10.1038/4315. PMID 9853615.
• Verschueren K, Remacle JE, Collart C, Kraft H, Baker BS, Tylzanowski P, Nelles L, Wuytens G, Su MT, Bodmer R, Smith JC, Huylebroeck D (July 1999). "SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5'-CACCT sequences in candidate target genes". The Journal of Biological Chemistry 274 (29): 20489–98. doi:10.1074/jbc.274.29.20489. PMID 10400677.
• Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H, Kitoh H, Mutoh N, Yamanaka T, Mushiake K, Kato K, Sonta S, Nagaya M (April 2001). "Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease". Nature Genetics 27 (4): 369–70. doi:10.1038/86860. PMID 11279515.
• Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F (June 2001). "The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion". Molecular Cell 7 (6): 1267–78. doi:10.1016/S1097-2765(01)00260-X. PMID 11430829.
• Cacheux V, Dastot-Le Moal F, Kääriäinen H, Bondurand N, Rintala R, Boissier B, Wilson M, Mowat D, Goossens M (July 2001). "Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease". Human Molecular Genetics 10 (14): 1503–10. doi:10.1093/hmg/10.14.1503. PMID 11448942.
• Tylzanowski P, Verschueren K, Huylebroeck D, Luyten FP (October 2001). "Smad-interacting protein 1 is a repressor of liver/bone/kidney alkaline phosphatase transcription in bone morphogenetic protein-induced osteogenic differentiation of C2C12 cells". The Journal of Biological Chemistry 276 (43): 40001–7. doi:10.1074/jbc.M104112200. PMID 11477103.
• Yamada K, Yamada Y, Nomura N, Miura K, Wakako R, Hayakawa C, Matsumoto A, Kumagai T, Yoshimura I, Miyazaki S, Kato K, Sonta S, Ono H, Yamanaka T, Nagaya M, Wakamatsu N (December 2001). "Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features". American Journal of Human Genetics 69 (6): 1178–85. doi:10.1086/324343. PMC 1235530. PMID 11592033.
• Amiel J, Espinosa-Parrilla Y, Steffann J, Gosset P, Pelet A, Prieur M, Boute O, Choiset A, Lacombe D, Philip N, Le Merrer M, Tanaka H, Till M, Touraine R, Toutain A, Vekemans M, Munnich A, Lyonnet S (December 2001). "Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures". American Journal of Human Genetics 69 (6): 1370–7. doi:10.1086/324342. PMC 1235547. PMID 11595972.
• Zweier C, Albrecht B, Mitulla B, Behrens R, Beese M, Gillessen-Kaesbach G, Rott HD, Rauch A (March 2002). ""Mowat-Wilson" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene". American Journal of Medical Genetics 108 (3): 177–81. doi:10.1002/ajmg.10226. PMID 11891681.
• Nagaya M, Kato J, Niimi N, Tanaka S, Wakamatsu N (August 2002). "Clinical features of a form of Hirschsprung's disease caused by a novel genetic abnormality". Journal of Pediatric Surgery 37 (8): 1117–22. doi:10.1053/jpsu.2002.34455. PMID 12149685.
• Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, Sancho E, Dedhar S, De Herreros AG, Baulida J (October 2002). "Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression". The Journal of Biological Chemistry 277 (42): 39209–16. doi:10.1074/jbc.M206400200. PMID 12161443.
• Espinosa-Parrilla Y, Amiel J, Augé J, Encha-Razavi F, Munnich A, Lyonnet S, Vekemans M, Attié-Bitach T (June 2002). "Expression of the SMADIP1 gene during early human development". Mechanisms of Development 114 (1-2): 187–91. doi:10.1016/S0925-4773(02)00062-X. PMID 12175509.
• Yoneda M, Fujita T, Yamada Y, Yamada K, Fujii A, Inagaki T, Nakagawa H, Shimada A, Kishikawa M, Nagaya M, Azuma T, Kuriyama M, Wakamatsu N (November 2002). "Late infantile Hirschsprung disease-mental retardation syndrome with a 3-bp deletion in ZFHX1B". Neurology 59 (10): 1637–40. doi:10.1212/01.wnl.0000034842.78350.4e. PMID 12451214.
• Postigo AA (May 2003). "Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway". The EMBO Journal 22 (10): 2443–52. doi:10.1093/emboj/cdg225. PMC 155983. PMID 12743038.
• Postigo AA, Depp JL, Taylor JJ, Kroll KL (May 2003). "Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins". The EMBO Journal 22 (10): 2453–62. doi:10.1093/emboj/cdg226. PMC 155984. PMID 12743039.
• Zweier C, Temple IK, Beemer F, Zackai E, Lerman-Sagie T, Weschke B, Anderson CE, Rauch A (August 2003). "Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat-Wilson syndrome". Journal of Medical Genetics 40 (8): 601–5. doi:10.1136/jmg.40.8.601. PMC 1735564. PMID 12920073.

External links

• GeneReviews/NIH/NCBI/UW entry on Mowat-Wilson syndrome
• ZEB2 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)