Gene name - Ror
Synonyms - dror
Cytological map position - 31B-32A
Function - receptor
Keyword(s) - neural
Symbol - Ror
Genetic map position - 2-33
Classification - receptor tyrosine kinase
Cellular location - surface
ROR proteins are conserved receptor tyrosine kinases (RTKs) characterized by an extracellular Fz domain [also called cysteine-rich-domain (CRD)], an immunoglobulin (Ig) domain, and a kringle domain. Mutations in ROR genes cause developmental defects including skeletal abnormalities in mice and humans. Studies of vertebrate RORs showed that the ROR CRD, like the Fz CRD, can bind to Wnts (Billiard, 2005; Hikasa, 2002; Kani, 2004; Mikels, 2006a; Oishi, 2003). In cell culture, ROR2 abrogates expression of a canonical Wnt reporter (Billiard, 2005; Mikels, 2006a; Green, 2007 and references therein).
Drosophila Dror encodes a putative receptor tyrosine kinase (RTK) and maps to cytological location 31B/C on the second chromosome. In embryos, this gene is expressed specifically in the developing nervous system. The Dror protein appears to be a homolog of two human RTKs, Rorl and Ror2. Dror and Rorl proteins share 36% amino acid identity in their extracellular domains and 61% identity in their catalytic tyrosine kinase (TK) domains. Rorl and Ror2 were originally identified on the basis of the similarity of their TK domains to the TK domains of members of the Trk family of neurotrophin receptors. The Dror protein shows even greater similarity to the Trk proteins within this region than do the human Ror proteins. In light of its similarity to trk and its neural-specific expression pattern, it is suggestd that Dror may encode a neurotrophic receptor that functions during early stages of neural development in Drosophila (Wilson, 1993).
Dror shows extensive sequence similarity to vertebrate Ror proteins throughout its length; however, Rorl and Ror2 include additional motifs at the extreme amino-terminal and carboxyl-terminal ends. Like the vertebrate Ror proteins, the extracellular domain of Dror contains a kringle domain and a Ror-like cysteine-containing domain. Other RTKs, such as the members of the EGF receptor family and insulin receptor family, are also characterized by extracellular cysteine-containing domains, but these are not obviously related to the domains in the Ror family of RTKs. A unique feature of the cysteine-containing domain in Dror is that it is interrupted by a 55-aa lysine-rich insertion of unknown function. The role of the single kringle domain adjacent to the transmembrane domain is also unclear (Wilson, 1993).
Generally genes encode clusters of kringle domains and, unlike the Ror RTKs, these are associated with a serine protease-like domain. The presence of a kringle domain in Dror is of particular interest, since proteins with kringle domains have not previously been identified in invertebrates (Wilson, 1993).
The Dror TK domain is most similar to the TK domains of vertebrate Ror and Trk proteins, showing 7%-16% greater identity with these proteins than with TK domains in the closely related insulin receptor family. In fact, the Ror and Trk TK domains show more similarity to the TK domain of Dror than they do to each other. However, surprisingly, the small number of amino acid substitutions that are specific either to the members of the Ror family or to the members of the Trk family and have therefore been suggested to be characteristic of a particular receptor group within the Trk-like superfamily are generally not present in Dror. One possible interpretation of these data is that the Ror and Trk families of RTKs developed their limited number of unique features after the chordate line diverged from arthropods in evolution. Searches for additional trk-related genes in Drosophila with Dror probes, employing conditions that have previously been used successfully to identify vertebrate trk genes and Dtrk, a second Drosophila Trk-family member (off-track), have thus far failed to identify a second ror gene or any additional trk-related genes in flies (Wilson, 1993).
The previously characterized Drosophila gene Dtrk appears to encode a distant relative of the Trk family, with 9 of the 40 most conserved amino acids in TK domains altered and <40% identity with vertebrate Trk TK domains. However, unlike Dror, Dtrk does show limited similarity (<25% identity) to the Trk proteins in its extracellular domain, even though its activation may be mediated by cell adhesion rather than by a neurotrophic factor (Wilson, 1993 and references therein).
The expression patterns of the vertebrate ror genes have not been reported, although ror cDNA clones were originally isolated from a human neuroblastoma cell line. The relatedness of the TK domains of both the vertebrate and Drosophila Ror proteins to Trk TK domains makes it attractive to speculate that the ror genes play a role in neural development. The observation that Dror expression in embryos is restricted to the nervous system is consistent with this idea. It is suggested that at least some of the amino acids that are found in both Trk and Ror TK domains, but rarely in other TK domains, have therefore probably evolved to mediate neural-specific functions. However, in the electric ray Torpedo californica, a RTK with a Trk-like TK domain has recently been identified that is expressed specifically in muscle and not in neurons. One untested explanation for this discrepancy is that the Torpedo receptor may be localized to the neuromuscular junction, a subcellular specialization that shares several functional properties with neurons (Wilson, 1993).
Since the vertebrate and Drosophila Ror proteins are so similar in their extracellular domains, it is likely that their ligands are also structurally related. It is not known whether these ligands are diffusible, like the neurotrophins, or are cell surface molecules with a more limited signaling range. Further, although the similarity of Trk and Ror TK domains suggests that some of their intracellular neural-specific functions are related, it is not clear which functions the Ror proteins may share with neurotrophin receptors. The peak of embryonic Dror expression (8-12 hr) starts before and overlaps with the period when early processes of neural differentiation, such as axonogenesis, occur in flies (9-10 hr onwards). Interestingly, vertebrate ror genes are also expressed relatively early in development, some time before the trk genes. Therefore, the Ror proteins probably play an important role in early neural differentiation and may be less involved in the later processes of neuronal cell survival that are commonly associated with the neurotrophin receptors (Wilson, 1993).
It is anticipated that a genetic analysis of Dror in Drosophila should address these issues and contribute to an understanding of the function of the Trk-like receptor superfamily in all higher eukaryotes (Wilson, 1993).
A third receptor tyrosine kinase has been characterized and termed 'Dnrk,' for Drosophila Neurospecific receptor kinase. Dnrk is expressed specifically in the developing nervous system following germ band elongation. The expression is restricted to the layer of neural progenitor cells between the epidermal and mesodermal cell layers. Expression is found in the brain, the ventral cord and late in embryogenesis in the peripheral nervous system. The distribution of transcripts after germ band shortening matches the profile of developing commisures and connectives. The extracellular domain of Dnrk protein exhibits a high degree of homology with those of Dror and human Rors. Dnrk possesses two conserved extracellular cysteine-containing domains and an extracellular kringle domain, resembling those observed in the Ror family of RTKs. All 16 cysteins in Dnrk are found in equivalent positions in Dror, Ror1 and Ror2. Dnrk protein contains the catalytic tyrosine kinase domain with two putative ATP-binding motifs, resembling those observed in Dtrk. The TK domain of Dnrk exhibits autophosphorylation activities in vitro. The TK domain shows about 40-45% identity to the corresponding domains of TrkB, Ror1, Ror2 and Dror. An altered TK domain, lacking the distal ATP-binding motif, also exhibits autophosphorylation activities, but to a lesser extent than wild type Dnrk. In addition to its TK activity, there are several putative tyrosine-containing motifs that upon phosphorylation may interact with Src homology 2 regions of other signaling molecules (Oishi, 1997).
Bases in 5' UTR -129
Bases in 3' UTR - 88
The protein consists of an extracellular cysteine-containing region, a kringle domain (a type of protein interactin domain), five potential N-glycosylation sites, a hydrophobic transmembrane domain and an intracellular putative tyrosine kinase domain. The amino terminal portion has a hydrophobic signal peptide involved in secretion across microsomal membranes during protein synthesis (Wilson, 1993).
The tyrosine kinase domain is similar to the TK domain of the vertebrate Trk family and the two human Ror proteins. Dror intracellular segment does not include a tyrosine for autophosphorylation. It shares a kringle domain with vertebrate Ror, but Dror has no immunoglobulin domain homologous to that of vertebrate Ror, nor does it contain the carboxyl-terminal serine (threonine-rich and proline rich domains present in Ror1 and Ror2) (Wilson, 1993).
date revised: 10 April 2008
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