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ROR2 (receptor tyrosine kinase-like orphan receptor 2)

Identity

Other namesBDB
BDB1
MGC163394
NTRKR2
HGNC (Hugo) ROR2
LocusID (NCBI) 4920
Location 9q22.31
Location_base_pair Starts at 94484878 and ends at 94712444 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Orientation: minus strand.

DNA/RNA

Description ROR2 contains 9 exons and is 227561 base pairs (via GeneLoc).
Transcription Five (5) alternative splice variants have been identified for ROR2.

Protein

 
  Extracellularly, ROR2 contains an Ig-like domain (Ig), a frizzled or cysteine-rich (CRD) domain shown to act as a receptor for Wnt and a kringle (Kr) domain. The extracellular and intracellular domains are separated by a transmembrane (TM) domain. Intracellularly, ROR2 contains a tyrosine kinase (TK) domain and a proline-rich domain (PR) flanked by serine/threonine (ST) rich domains.
Description The ROR2 protein product is 943 amino acids with the molecular weight estimated to be 104.76 kDa.
Expression ROR2 is a developmentally expressed kinase with high expression normally seen throughout the body including the face, limb buds, heart, lungs and brain (Takeuchi et al., 2000; Matsuda et al., 2001). Expression of ROR2 begins to abate at approximately day 16 of development (Yoda et al., 2003).
In adult tissues, ROR2 is normally undetectable or expressed at very low levels. Functional ROR2 expression has been confirmed in the mouse cycling and pregnant uterus (Hatta et al., 2010). In humans, ROR2 cDNA has been detected in the uterus as well as the parathyroid and testis (Katoh et al., 2005). ROR2 has further been found to be upregulated as pluripotent cells emerge as pre-osteoblasts, and to be downregulated again as cells differentiate into osteocytes (Billiard et al., 2005).
Localisation ROR2 is a single-pass type I membrane protein (Masiakowski et al., 1992) with localization restricted to the membrane.
Function ROR2 is a tyrosine protein kinase receptor highly implicated in development. It has also been implicated in the early formation of chondrocytes (DeChiara et al., 2000; Takeuchi et al., 2000). ROR2 is thought to play a key role in cartilage and growth plate development (DeChiara et al., 2000). The Wnt signaling pathway has also emerged as a key target of ROR2 activity. More specifically, evidence suggests that Wnt5a utilizes ROR2 as a receptor or co-receptor for its noncanonical Wnt mediated signaling (Minami et al., 2010; Sato et al., 2010). Additionally, recent evidence suggests that ROR2 is expressed and plays a role in various cancer etiologies including gastric cancer, renal cell carcinoma, malignant melanoma, and prostate cancer.
Homology ROR2 is highly conserved across several species - from C. elegans to D. melanogaster to M. musculus to H. sapiens. For example, there is a 92% amino acid identity between mouse and human ROR2 (Yoda et al., 2003).

Mutations

Note Robinow syndrome and Brachydactyl type B (BDB) are two genetic disorders that arise from mutations in ROR2:
1) Robinow syndrome is an autosomal recessive disorder that arises from nonsense, missense and frameshift mutations in the kringle, CRD and kinase domains - and is thought to cause a loss of function of ROR2 (Afzal et al., 2000). Those that present with Robinow syndrome have skeletal development defects (van Bokhoven et al., 2000; Afzal et al., 2003; Schwabe et al., 2004). This is seen within developmentally regulated features such as the formation of bones in the face and limbs.
2) BDB is an autosomal dominant disorder that arises from truncations of the kinase domains - either truncation of the serine/threonine domains and proline rich domain just below the Tyr kinase domain; or truncation of the entire intracellular domain right just below the transmembrane domain (Oldridge et al., 2000). Patients that present with BDB have abnormally short digits with the 4th and 5th digits particularly affected and have malformed or absent finger and toe nails (Schwabe et al., 2000; Afzal et al., 2003).
Somatic Kubo et al. has reported somatic mutations in ROR2 in invasive gastric cancers (Kubo et al., 2009).

Implicated in

Entity Gastric cancers
Note ROR2 has been identified in poorly differentiated invasive gastric cancer and in intestinal-type and diffuse-type gastric cancers. ROR2 is identified as a frequent target of somatic mutations in poorly differentiated invasive gastric cancers (Kubo et al., 2009). In intestinal-type and diffuse-type gastric cancers, ROR2 is shown to play a role in cell invasion and is also downstream of the crosstalk between the Hedgehog and Wnt signaling pathways (Ohta et al., 2009).
  
Entity Metastatic melanoma
Note ROR2 was found to be overexpressed in a majority of metastatic malignant melanomas and also found to have a dramatic impact on cell motility, cell invasion and metastasis. Additionally, ROR2 expression was found to be correlated with Wnt5a expression in metastatic melanoma (O'Connell et al., 2010).
  
Entity Osteosarcoma
Note ROR2 overexpression has been described in this adolescent bone cancer. ROR2 is transactivated in a majority of osteosarcoma and also plays a role in cell migration and cell proliferation (Morioka et al., 2009). Evidence links Wnt5a and ROR2 within osteosarcoma where ROR2 has additional ties to having a role in the degradation of the extracellular matrix and invadopia formation (Enomoto et al., 2009).
  
Entity Prostate cancer
Note ROR2 has also been linked to prostate cancer via Wnt5a interaction. In prostate cancer, evidence suggests that Wnt5a utilizes ROR2 or Frizzled 2 as a receptor for its invasive potential. Further, it was shown that the Wnt5a/ROR2 receptor complex has a role in cell invasion (Yamamoto et al., 2010).
  
Entity Renal cell carcinoma
Note ROR2 was found to be overexpressed in the majority of renal cell carcinoma primary tumors. This aberrantly overexpressed kinase was shown to support cell migration, affect anchorage independent growth and promote xenograft tumor growth in renal cell carcinoma cell lines (Wright et al., 2009).
  
Entity Squamous cell carcinoma
Note ROR2 has been shown to be more highly invasive in oral malignant cancer epithelial cells than normal mucosa. In this cancer, ROR2 is associated with increased cell polarity and cell motility (Kobayashi et al., 2009).
  

External links

Nomenclature
HGNC (Hugo)ROR2   10257
Cards
AtlasROR2ID43476ch9q22
Entrez_Gene (NCBI)ROR2  4920  receptor tyrosine kinase-like orphan receptor 2
GeneCards (Weizmann)ROR2
Ensembl (Hinxton)ENSG00000169071 [Gene_View]  chr9:94484878-94712444 [Contig_View]  ROR2 [Vega]
AceView (NCBI)ROR2
Genatlas (Paris)ROR2
WikiGenes4920
SOURCE (Princeton)NM_004560
Genomic and cartography
GoldenPath (UCSC)ROR2  -  9q22.31   chr9:94484878-94712444 -  9q22   [Description]    (hg19-Feb_2009)
EnsemblROR2 - 9q22 [CytoView]
Mapping of homologs : NCBIROR2 [Mapview]
OMIM113000   268310   602337   
Gene and transcription
Genbank (Entrez)AA463746 AA626834 AB209154 BC033697 BC051273
RefSeq transcript (Entrez)NM_004560
RefSeq genomic (Entrez)AC_000141 NC_000009 NC_018920 NG_008089 NT_008470 NW_001839229 NW_004929366
Consensus coding sequences : CCDS (NCBI)ROR2
Cluster EST : UnigeneHs.644776 [ NCBI ]
CGAP (NCI)Hs.644776
Alternative Splicing : Fast-db (Paris)GSHG0030950
Alternative Splicing GalleryENSG00000169071
Gene ExpressionROR2 [ NCBI-GEO ]     ROR2 [ SEEK ]   ROR2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ01974 (Uniprot)
NextProtQ01974  [Medical]
With graphics : InterProQ01974
Splice isoforms : SwissVarQ01974 (Swissvar)
Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)FZ (PS50038)    IG_LIKE (PS50835)    KRINGLE_1 (PS00021)    KRINGLE_2 (PS50070)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)   
Domains : Interpro (EBI)Frizzled_dom    Ig-like_dom    Ig-like_fold    Ig_I-set    Ig_sub2    Kinase-like_dom    Kringle    Kringle-like    Kringle_CS    Prot_kinase_dom    Ser-Thr/Tyr_kinase_cat_dom    Tyr_kinase_AS    Tyr_kinase_cat_dom    Tyr_kinase_rcpt_ROR   
Related proteins : CluSTrQ01974
Domain families : Pfam (Sanger)Fz (PF01392)    I-set (PF07679)    Kringle (PF00051)    Pkinase_Tyr (PF07714)   
Domain families : Pfam (NCBI)pfam01392    pfam07679    pfam00051    pfam07714   
Domain families : Smart (EMBL)IGc2 (SM00408)  KR (SM00130)  TyrKc (SM00219)  
DMDM Disease mutations4920
Blocks (Seattle)Q01974
PDB (SRS)3ZZW    4GT4   
PDB (PDBSum)3ZZW    4GT4   
PDB (IMB)3ZZW    4GT4   
PDB (RSDB)3ZZW    4GT4   
Human Protein AtlasENSG00000169071
Peptide AtlasQ01974
HPRD03822
IPIIPI00304999   IPI00480153   
Protein Interaction databases
DIP (DOE-UCLA)Q01974
IntAct (EBI)Q01974
FunCoupENSG00000169071
BioGRIDROR2
InParanoidQ01974
Interologous Interaction database Q01974
IntegromeDBROR2
STRING (EMBL)ROR2
Ontologies - Pathways
Ontology : AmiGOcartilage condensation  somitogenesis  transmembrane receptor protein tyrosine kinase activity  frizzled binding  protein binding  ATP binding  integral to plasma membrane  signal transduction  transmembrane receptor protein tyrosine kinase signaling pathway  Wnt receptor signaling pathway, calcium modulating pathway  JNK cascade  multicellular organismal development  negative regulation of cell proliferation  Wnt-protein binding  cell differentiation  positive regulation of cell migration  embryonic genitalia morphogenesis  inner ear morphogenesis  positive regulation of transcription, DNA-dependent  Wnt receptor signaling pathway, planar cell polarity pathway  negative regulation of canonical Wnt receptor signaling pathway  positive regulation of canonical Wnt receptor signaling pathway  
Ontology : EGO-EBIcartilage condensation  somitogenesis  transmembrane receptor protein tyrosine kinase activity  frizzled binding  protein binding  ATP binding  integral to plasma membrane  signal transduction  transmembrane receptor protein tyrosine kinase signaling pathway  Wnt receptor signaling pathway, calcium modulating pathway  JNK cascade  multicellular organismal development  negative regulation of cell proliferation  Wnt-protein binding  cell differentiation  positive regulation of cell migration  embryonic genitalia morphogenesis  inner ear morphogenesis  positive regulation of transcription, DNA-dependent  Wnt receptor signaling pathway, planar cell polarity pathway  negative regulation of canonical Wnt receptor signaling pathway  positive regulation of canonical Wnt receptor signaling pathway  
REACTOMEROR2
Protein Interaction DatabaseROR2
Wikipedia pathwaysROR2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ROR2
SNP (GeneSNP Utah)ROR2
SNP : HGBaseROR2
Genetic variants : HAPMAPROR2
1000_GenomesROR2 
ICGC programENSG00000169071 
Somatic Mutations in Cancer : COSMICROR2 
CONAN: Copy Number AnalysisROR2 
Mutations and Diseases : HGMDROR2
OMIM113000    268310    602337   
GENETestsROR2
Disease Genetic AssociationROR2
Huge Navigator ROR2 [HugePedia]  ROR2 [HugeCancerGEM]
Genomic VariantsROR2  ROR2 [DGVbeta]
Exome VariantROR2
dbVarROR2
ClinVarROR2
snp3D : Map Gene to Disease4920
General knowledge
Homologs : HomoloGeneROR2
Homology/Alignments : Family Browser (UCSC)ROR2
Phylogenetic Trees/Animal Genes : TreeFamROR2
Chemical/Protein Interactions : CTD4920
Chemical/Pharm GKB GenePA34629
Clinical trialROR2
Cancer Resource (Charite)ENSG00000169071
Other databases
Probes
Litterature
PubMed69 Pubmed reference(s) in Entrez
CoreMineROR2
iHOPROR2

Bibliography

A novel family of cell surface receptors with tyrosine kinase-like domain.
Masiakowski P, Carroll RD.
J Biol Chem. 1992 Dec 25;267(36):26181-90.
PMID 1334494
 
Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.
Afzal AR, Rajab A, Fenske CD, Oldridge M, Elanko N, Ternes-Pereira E, Tuysuz B, Murday VA, Patton MA, Wilkie AO, Jeffery S.
Nat Genet. 2000 Aug;25(4):419-22.
PMID 10932186
 
Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development.
DeChiara TM, Kimble RB, Poueymirou WT, Rojas J, Masiakowski P, Valenzuela DM, Yancopoulos GD.
Nat Genet. 2000 Mar;24(3):271-4.
PMID 10700181
 
Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.
Oldridge M, Fortuna AM, Maringa M, Propping P, Mansour S, Pollitt C, DeChiara TM, Kimble RB, Valenzuela DM, Yancopoulos GD, Wilkie AO.
Nat Genet. 2000 Mar;24(3):275-8.
PMID 10700182
 
Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
Schwabe GC, Tinschert S, Buschow C, Meinecke P, Wolff G, Gillessen-Kaesbach G, Oldridge M, Wilkie AO, Komec R, Mundlos S.
Am J Hum Genet. 2000 Oct;67(4):822-31. Epub 2000 Sep 12.
PMID 10986040
 
Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation.
Takeuchi S, Takeda K, Oishi I, Nomi M, Ikeya M, Itoh K, Tamura S, Ueda T, Hatta T, Otani H, Terashima T, Takada S, Yamamura H, Akira S, Minami Y.
Genes Cells. 2000 Jan;5(1):71-8.
PMID 10651906
 
Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.
van Bokhoven H, Celli J, Kayserili H, van Beusekom E, Balci S, Brussel W, Skovby F, Kerr B, Percin EF, Akarsu N, Brunner HG.
Nat Genet. 2000 Aug;25(4):423-6.
PMID 10932187
 
Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development.
Matsuda T, Nomi M, Ikeya M, Kani S, Oishi I, Terashima T, Takada S, Minami Y.
Mech Dev. 2001 Jul;105(1-2):153-6.
PMID 11429290
 
One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B.
Afzal AR, Jeffery S.
Hum Mutat. 2003 Jul;22(1):1-11.
PMID 12815588
 
Expression and function of the Ror-family receptor tyrosine kinases during development: lessons from genetic analyses of nematodes, mice, and humans.
Yoda A, Oishi I, Minami Y.
J Recept Signal Transduct Res. 2003 Feb;23(1):1-15. (REVIEW)
PMID 12680586
 
Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
Schwabe GC, Trepczik B, Suring K, Brieske N, Tucker AS, Sharpe PT, Minami Y, Mundlos S.
Dev Dyn. 2004 Feb;229(2):400-10.
PMID 14745966
 
The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells.
Billiard J, Way DS, Seestaller-Wehr LM, Moran RA, Mangine A, Bodine PV.
Mol Endocrinol. 2005 Jan;19(1):90-101. Epub 2004 Sep 23.
PMID 15388793
 
Comparative genomics on ROR1 and ROR2 orthologs.
Katoh M, Katoh M.
Oncol Rep. 2005 Nov;14(5):1381-4.
PMID 16211313
 
Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling.
Enomoto M, Hayakawa S, Itsukushima S, Ren DY, Matsuo M, Tamada K, Oneyama C, Okada M, Takumi T, Nishita M, Minami Y.
Oncogene. 2009 Sep 10;28(36):3197-208. Epub 2009 Jun 29.
PMID 19561643
 
Ror2 expression in squamous cell carcinoma and epithelial dysplasia of the oral cavity.
Kobayashi M, Shibuya Y, Takeuchi J, Murata M, Suzuki H, Yokoo S, Umeda M, Minami Y, Komori T.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Mar;107(3):398-406.
PMID 19217015
 
Resequencing and copy number analysis of the human tyrosine kinase gene family in poorly differentiated gastric cancer.
Kubo T, Kuroda Y, Shimizu H, Kokubu A, Okada N, Hosoda F, Arai Y, Nakamura Y, Taniguchi H, Yanagihara K, Imoto I, Inazawa J, Hirohashi S, Shibata T.
Carcinogenesis. 2009 Nov;30(11):1857-64. Epub 2009 Sep 4.
PMID 19734198
 
Orphan receptor tyrosine kinase ROR2 as a potential therapeutic target for osteosarcoma.
Morioka K, Tanikawa C, Ochi K, Daigo Y, Katagiri T, Kawano H, Kawaguchi H, Myoui A, Yoshikawa H, Naka N, Araki N, Kudawara I, Ieguchi M, Nakamura K, Nakamura Y, Matsuda K.
Cancer Sci. 2009 Jul;100(7):1227-33. Epub 2009 Apr 15.
PMID 19486338
 
Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers.
Ohta H, Aoyagi K, Fukaya M, Danjoh I, Ohta A, Isohata N, Saeki N, Taniguchi H, Sakamoto H, Shimoda T, Tani T, Yoshida T, Sasaki H.
Br J Cancer. 2009 Jan 27;100(2):389-98. Epub 2008 Dec 23.
PMID 19107131
 
Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma.
Wright TM, Brannon AR, Gordan JD, Mikels AJ, Mitchell C, Chen S, Espinosa I, van de Rijn M, Pruthi R, Wallen E, Edwards L, Nusse R, Rathmell WK.
Oncogene. 2009 Jul 9;28(27):2513-23. Epub 2009 May 18.
PMID 19448672
 
Orphan receptor kinase ROR2 is expressed in the mouse uterus.
Hatta K, Chen Z, Carter AL, Leno-Duran E, Zhang J, Ruiz-Ruiz C, Olivares EG, MacLeod RJ, Croy BA.
Placenta. 2010 Apr;31(4):327-33. Epub 2010 Feb 10.
PMID 20149452
 
Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases.
Minami Y, Oishi I, Endo M, Nishita M.
Dev Dyn. 2010 Jan;239(1):1-15. (REVIEW)
PMID 19530173
 
The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma.
O'Connell MP, Fiori JL, Xu M, Carter AD, Frank BP, Camilli TC, French AD, Dissanayake SK, Indig FE, Bernier M, Taub DD, Hewitt SM, Weeraratna AT.
Oncogene. 2010 Jan 7;29(1):34-44. Epub 2009 Oct 5.
PMID 19802008
 
Wnt5a regulates distinct signalling pathways by binding to Frizzled2.
Sato A, Yamamoto H, Sakane H, Koyama H, Kikuchi A.
EMBO J. 2010 Jan 6;29(1):41-54. Epub 2009 Nov 12.
PMID 19910923
 
Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase.
Yamamoto H, Oue N, Sato A, Hasegawa Y, Yamamoto H, Matsubara A, Yasui W, Kikuchi A.
Oncogene. 2010 Apr 8;29(14):2036-46. Epub 2010 Jan 18.
PMID 20101234
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written07-2010Tricia M Wright, W Kimryn Rathmell
Department of Genetics, Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA

Citation

This paper should be referenced as such :
Wright TM, Rathmell WK . ROR2 (receptor tyrosine kinase-like orphan receptor 2). Atlas Genet Cytogenet Oncol Haematol. July 2010 .
URL : http://AtlasGeneticsOncology.org/Genes/ROR2ID43476ch9q22.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44997/1/07-2010-ROR2ID43476ch9q22.pdf   [ Bibliographic record ]

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indexed on : Wed Apr 16 11:26:49 CEST 2014

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