ROR2 (receptor tyrosine kinase-like orphan receptor 2)

2010-07-01   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





ROR2 contains 9 exons and is 227561 base pairs (via GeneLoc).


Five (5) alternative splice variants have been identified for ROR2.


Atlas Image
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.


The ROR2 protein product is 943 amino acids with the molecular weight estimated to be 104.76 kDa.


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).


ROR2 is a single-pass type I membrane protein (Masiakowski et al., 1992) with localization restricted to the membrane.


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.


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).



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).


Kubo et al. has reported somatic mutations in ROR2 in invasive gastric cancers (Kubo et al., 2009).

Implicated in

Entity name
Gastric cancers
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 name
Metastatic melanoma
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 (OConnell et al., 2010).
Entity name
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 name
Prostate cancer
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 name
Renal cell carcinoma
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 name
Squamous cell carcinoma
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).


Pubmed IDLast YearTitleAuthors
128155882003One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B.Afzal AR et al
109321862000Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.Afzal AR et al
153887932005The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells.Billiard J et al
107001812000Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development.DeChiara TM et al
195616432009Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling.Enomoto M et al
201494522010Orphan receptor kinase ROR2 is expressed in the mouse uterus.Hatta K et al
162113132005Comparative genomics on ROR1 and ROR2 orthologs.Katoh M et al
192170152009Ror2 expression in squamous cell carcinoma and epithelial dysplasia of the oral cavity.Kobayashi M et al
197341982009Resequencing and copy number analysis of the human tyrosine kinase gene family in poorly differentiated gastric cancer.Kubo T et al
13344941992A novel family of cell surface receptors with tyrosine kinase-like domain.Masiakowski P et al
114292902001Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development.Matsuda T et al
195301732010Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases.Minami Y et al
194863382009Orphan receptor tyrosine kinase ROR2 as a potential therapeutic target for osteosarcoma.Morioka K et al
198020082010The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma.O'Connell MP et al
191071312009Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers.Ohta H et al
107001822000Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.Oldridge M et al
199109232010Wnt5a regulates distinct signalling pathways by binding to Frizzled2.Sato A et al
147459662004Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.Schwabe GC et al
106519062000Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation.Takeuchi S et al
194486722009Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma.Wright TM et al
201012342010Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase.Yamamoto H et al
126805862003Expression and function of the Ror-family receptor tyrosine kinases during development: lessons from genetic analyses of nematodes, mice, and humans.Yoda A et al
109321872000Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.van Bokhoven H et al

Other Information

Locus ID:

NCBI: 4920
MIM: 602337
HGNC: 10257
Ensembl: ENSG00000169071


dbSNP: 4920
ClinVar: 4920
TCGA: ENSG00000169071


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
Beta-catenin independent WNT signalingREACTOMER-HSA-3858494
PCP/CE pathwayREACTOMER-HSA-4086400
WNT5A-dependent internalization of FZD2, FZD5 and ROR2REACTOMER-HSA-5140745

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
198020082010The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma.78
241040622013Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2.75
266907022016Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation.56
195616432009Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling.53
186155872008Wnt5a induces homodimerization and activation of Ror2 receptor tyrosine kinase.42
153887932005The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells.40
213423702011Critical role of Wnt5a-Ror2 signaling in motility and invasiveness of carcinoma cells following Snail-mediated epithelial-mesenchymal transition.40
194486722009Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma.39
281270512017Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness.35
182153202008Ror2 modulates the canonical Wnt signaling in lung epithelial cells through cooperation with Fzd2.34


Tricia M Wright ; W Kimryn Rathmell

ROR2 (receptor tyrosine kinase-like orphan receptor 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-07-01

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