Ror receptor tyrosine kinases: orphans no more

Abstract

Receptor tyrosine kinase-like orphan receptor (Ror) proteins are a conserved family of tyrosine kinase receptors that function in developmental processes including skeletal and neuronal development, cell movement and cell polarity. Although Ror proteins were originally named because the associated ligand and signaling pathway were unknown, recent studies in multiple species have now established that Ror proteins are Wnt receptors. Depending on the cellular context, Ror proteins can either activate or repress transcription of Wnt target genes and can modulate Wnt signaling by sequestering Wnt ligands. New evidence implicates Ror proteins in planar cell polarity, an alternative Wnt pathway. Here, we review the progress made in understanding these mysterious proteins and, in particular, we focus on their function as Wnt receptors.

Figure 1. Structure of Ror RTKs in different species

Structure of Ror receptor tyrosine kinases (RTKs) in different species. Domain organization (approximately to scale) of Ror proteins in human (hROR1, hROR2), mouse (mRor1, mRor2), C. elegans (CAM-1) and Drosophila (dROR). The N-terminal extracellular domain (ECD) is above and the intracellular domain (ICD) is below the double line representing the plasma membrane (image adapted from Refs [68, 69]).

Figure 2

Ror proteins as Wnt receptors

Figure 3

Other Ror functions

Box Figure 1. The different families within the NTRK superfamily of tyrosine kinases

The tree, which has no root, represents an approximation of the evolutionary divergence, as different domains within the proteins have evolved at different rates in different species and have experienced independent introductions of the Ig domain. Highlighted are the NTRK (blue), Ddr (green), MuSK/Nrk (red), and Ror (yellow) families; each line represents a single protein from a species in the labelled clade (i.e. the three lines for nematode CAM-1 represent CAM-1 of C. elegans, Brugia malayi, and Pristionchus pacificus). The sponge Frizzled-Kringle protein (black) does not fit into any family. Sequences are from GenBank (http://www.ncbi.nlm.nih.gov/sites/entrez), Ensembl (http://www.ensembl.org), UCSC Genome Browser (http://genome.ucsc.edu), and JGI (http://genome.jgi-psf.org). Tree generated by ClustalX (v1.83.1; [71]) and Phylodendron (v0.8d; http://iubio.bio.indiana.edu/treeapp/treeprint-form.html).