Disease relevance of Ror2

• BACKGROUNDS: Drosophila neurospecific receptor tyrosine kinases (RTKs), Dror and Dnrk, as well as Ror1 and Ror2 RTKs, isolated from human neuroblastoma, have been identified as a structurally related novel family of RTKs (Ror-family RTKs) [1].
• RESULTS: Both Ror2-/- and Wnt5a-/- mice exhibit dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects [2].

High impact information on Ror2

• Further, we find that Ror2 is selectively expressed in the chondrocytes of all developing cartilage anlagen, where it essential during initial growth and patterning, as well as subsequently in the proliferating chondrocytes of mature growth plates, where it is required for normal expansion [3].
• Thus, Ror2 encodes a receptor-like tyrosine kinase that is selectively expressed in, and particularly important for, the chondrocyte lineage [3].
• The mammalian Ror family of receptor tyrosine kinases consists of two structurally related proteins, Ror1 and Ror2 [4].
• Interestingly, mRor1/mRor2 double mutant mice show markedly enhanced skeletal abnormalities compared with mRor2 mutant mice [4].
• Furthermore, double mutant mice also exhibit defects not observed in mRor2 mutant mice, including a sternal defect, dysplasia of the symphysis of the pubic bone, and complete transposition of the great arteries [4].

Biological context of Ror2

• As an attempt to gain insights into their roles in mouse development, expression patterns of Ror1 and Ror2 during early embryogenesis were examined and compared [5].
• Site-directed mutagenesis of tyrosine residues in Ror2 reveals that the sites of phosphorylation are contained among the five tyrosine residues in the proline-rich domain but not among the four tyrosine residues in the tyrosine kinase domain [6].
• Ror2, a member of the mammalian Ror family of receptor tyrosine kinases, plays important roles in developmental morphogenesis, although the mechanism underlying activation of Ror2 remains largely elusive [6].

Anatomical context of Ror2

• Immunocytochemical analysis indicated that Ror1 and Ror2 are highly concentrated in the growth cones of immature neurons and are present throughout the somatodendritic compartment of mature hippocampal cells [7].
• Interestingly, at early stages, Ror1 and Ror2 exhibit similar expression patterns in the developing face, including the frontonasal process and pharyngeal arches, which are derived from cephalic neural crest cells [5].
• At these times, Ror2 is expressed much more widely than Ror1, expression of which is largely restricted to head mesenchyme [8].
• Ror1 and Ror2 are both expressed in derivatives of all three germ layers and in most organ systems, including the nervous, circulatory, respiratory, digestive, urogenital and skeletal systems [8].
• Whole-mount in situ hybridization analysis showed that mRor2 was expressed in the branchial arches, heart and limb/tailbuds, in addition to the developing nervous system [9].

Associations of Ror2 with chemical compounds

• Furthermore, it was found that association of Ror2 with CKIepsilon is required for its serine/threonine phosphorylation by CKIepsilon [6].
• We also show that Ror2 is phosphorylated by CKIepsilon on serine/threonine residues, in its C-terminal serine/threonine-rich 2 domain, resulting in autophosphorylation of Ror2 on tyrosine residues [6].
• This association occurs primarily via the cytoplasmic C-terminal proline-rich domain of Ror2 [6].

Physical interactions of Ror2

• In vitro binding assay revealed that Wnt5a binds to the CRD of Ror2 [2].

Other interactions of Ror2

• Ror2 may thus act as a receptor for Wnt5a to activate non-canonical Wnt signalling [2].
• We show that when expressed in mammalian cells, Ror2 associates with casein kinase Iepsilon (CKIepsilon), a crucial regulator of Wnt signaling [6].
• Intriguingly, a mutant of Ror2 lacking five tyrosine residues, including the autophosphorylation sites, fails to tyrosine phosphorylate G protein-coupled receptor kinase 2 [6].
• We show that Ror2 (tyrosine kinase receptor) and BRI-b (serine/threonine kinase receptor) form a ligand independent heteromeric complex [10].

References