| Written | 2010-07 | Tricia M Wright, W Kimryn Rathmell |
| Department of Genetics, Curriculum in Genetics, Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA |
| Identity |
| Alias_names | NTRKR2 |
| BDB | |
| BDB1 | |
| receptor tyrosine kinase-like orphan receptor 2 | |
| Other alias | MGC163394 |
| HGNC (Hugo) | ROR2 |
| LocusID (NCBI) | 4920 |
| Atlas_Id | 43476 |
| Location | 9q22.31 [Link to chromosome band 9q22] |
| Location_base_pair | Starts at 91726447 and ends at 91950162 bp from pter ( according to hg19-Feb_2009) [Mapping ROR2.png] |
| Local_order | Orientation: minus strand. |
| Fusion genes (updated 2016) | FANCC (9q22.32) / ROR2 (9q22.31) | ROR2 (9q22.31) / KCNC2 (12q21.1) |
| 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 |
| Note | |
| 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). |
| Bibliography |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Comparative genomics on ROR1 and ROR2 orthologs. |
| Katoh M, Katoh M. |
| Oncol Rep. 2005 Nov;14(5):1381-4. |
| PMID 16211313 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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. 2011;15(4):341-343. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/ROR2ID43476ch9q22.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
|
Soft tissue tumors: an overview
|
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:17:15 CEST 2017 |
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