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Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: Their implications in developmental morphogenesis and human diseases

Corresponding Author

Yasuhiro Minami

[email protected]

Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan

Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanSearch for more papers by this author

Isao Oishi,

Isao Oishi

Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology, Osaka, Japan

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Mitsuharu Endo,

Mitsuharu Endo

Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan

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Michiru Nishita,

Michiru Nishita

Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan

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Yasuhiro Minami,

Corresponding Author

Yasuhiro Minami

[email protected]

Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan

Isao Oishi,

Isao Oishi

Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology, Osaka, Japan

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Mitsuharu Endo,

Mitsuharu Endo

Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan

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Michiru Nishita,

Michiru Nishita

Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan

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First published: 15 June 2009

https://doi.org/10.1002/dvdy.21991

Citations: 192

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Abstract

The Ror-family receptor tyrosine kinases (RTKs) play crucial roles in the development of various organs and tissues. In mammals, Ror2, a member of the Ror-family RTKs, has been shown to act as a receptor or coreceptor for Wnt5a to mediate noncanonical Wnt signaling. Ror2- and Wnt5a-deficient mice exhibit similar abnormalities during developmental morphogenesis, reflecting their defects in convergent extension movements and planar cell polarity, characteristic features mediated by noncanonical Wnt signaling. Furthermore, mutations within the human Ror2 gene are responsible for the genetic skeletal disorders dominant brachydactyly type B and recessive Robinow syndrome. Accumulating evidence demonstrate that Ror2 mediates noncanonical Wnt5a signaling by inhibiting the β-catenin-TCF pathway and activating the Wnt/JNK pathway that results in polarized cell migration. In this article, we review recent progress in understanding the roles of noncanonical Wnt5a/Ror2 signaling in developmental morphogenesis and in human diseases, including heritable skeletal disorders and tumor invasion. Developmental Dynamics 239:1–15, 2010. © 2009 Wiley-Liss, Inc.

STRUCTURE OF THE ROR-FAMILY RECEPTOR TYROSINE KINASES (RTKS)

The Ror-family of RTKs are type I transmembrane protein tyrosine kinases characterized by their extracellular Frizzled-like cysteine-rich domains (CRDs) and membrane-proximal Kringle domains (Fig. 1). The Ror-family RTKs are evolutionarily conserved in invertebrate and vertebrate, including Caenorhabditis elegans, Aplysia californica, Drosophila melanogaster, Danio rerio, Xenopus laevis, Gallus gallus, Mus musculus, and Homo sapiens (Masiakowski and Carroll,1992; Wilson et al.,1993; Forrester et al.,1999; Koga et al.,1999; Oishi et al.,1999; McKay et al.,2001b; Hikasa et al.,2002; Rodriguez-Niedenfuhr et al.,2004; Katoh,2005). In vertebrate, Ror-family RTKs consist of two structurally related members, Ror1 and Ror2.

Details are in the caption following the image — **Figure 1**
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Schematic representation of the structure of Ror-family receptor tyrosine kinases (RTKs) in vertebrate and invertebrate. Immunoglobulin-like (Ig-like) domains, Frizzled-like cysteine-rich (CRD) domains, Kringle domains, tyrosine kinase (TK) domains, proline-rich domains (PRD), and serine/threonine-rich domains (S/TRD1 and 2) are indicated.

The extracellular CRDs of the Ror-family RTKs have 10 conserved cysteine residues within ∼130 amino acids and exhibit similarities to the CRDs found in the Frizzled (Fzd) family of seven transmembrane Wnt receptors. In addition, the CRDs can also be found in the various soluble and transmembrane proteins, which play crucial roles in development, including secreted Frizzled-related proteins (sFRPs); muscle-specific receptor tyrosine kinase (MuSK); Smoothened (Smo), a coreceptor of Hedgehog signaling; carboxypeptidase Z (CPZ), a secreted metallocarboxypeptidase; and collagen XVIII (C18) (Masiakowski and Yancopoulos,1998; Rehn et al.,1998; Saldanha et al.,1998; Xu and Nusse,1998). The CRDs in sFRPs, CPZ, and cryptic polypeptide of C18 are indicated to bind with Wnt ligands physically, and these molecules modulate Wnt signaling (Bafico et al.,1999; Moeller et al.,2003; Wang et al.,2008). A series of studies demonstrate that Ror proteins can also interact with several Wnt ligands both physically and functionally, and the CRDs play a central role for these interaction (Hikasa et al.,2002; Oishi et al.,2003; Forrester et al.,2004; Kani et al.,2004; Billiard et al.,2005; Mikels and Nusse,2006; Green et al.,2007). In mammals, it has been shown that Ror2 acts as a receptor or coreceptor for Wnt5a and the CRD of Ror2 is required for binding to Wnt5a and mediating Wnt5a signaling to cell interior (Fig. 2; Oishi et al.,2003; Mikels and Nusse,2006). In addition, its CRD is essential for Ror2 binding to Frizzleds and BMP receptor type Ib, highlighting the importance of this domain in the function of the Ror-family RTKs, and suggesting that a variety of protein–protein interactions mediated by the CRDs are critical to elicit diverse cellular responses (Oishi et al.,2003; Sammar et al.,2004).

The membrane proximal Kringle domains consisting of ∼80 amino acids are also highly conserved throughout the Ror-family RTKs. The Kringle domain is characterized by a triple loop by means of triple disulfide-bridges and thought to play a role in binding to peptides, proteins, membranes, or phospholipids. This domain has been found in several proteins such as serine proteases involved in blood-clotting cascade, apolipoprotein(a), hepatocyte growth factor, and transmenbrane Kremen proteins (Patthy,1985; McLean et al.,1987; Furie and Furie,1988; Nakamura et al.,1989,2001). Kremen proteins were identified to be the receptors for Dickkopf (Dkk), which acts as an inhibitor of Wnt/β-catenin signaling (Mao et al.,2002). Although the function of the Kringle domain in Ror-family RTKs and Kremens are still elusive, the Kringle domains in Ror proteins are assumed to function as recognition modules for binding to another Wnt regulatory proteins.

In addition to the CRDs and Kringle domains, most of the Ror-family members, except Drosophila Rors (Dror and Dnrk), possess the immunoglobulin (Ig)-like domains in their N-terminal extracellular regions. The Ig-like domains are found in a large number of proteins and frequently involved in protein–protein and protein–ligand interactions. The Ig-like domains of the Ror-family RTKs may also contribute to binding to ligands and signaling molecules.

The cytoplasmic regions of the Ror-family RTKs contain conserved tyrosine kinase (TK) domains, which exhibit highest similarities to those of the tropomyosin-receptor-kinase (Trk) family, MuSK family, and discoidin-like domain receptor (Ddr) family (Robinson et al.,2000; Sossin,2006; Green et al.,2008b). Tyrosine kinase activity of Ror2 can be assessed by autophosphorylation and tyrosine phosphorylation of Ror2 substrate 14-3-3β, a scaffold protein (Kani et al.,2004; Billiard et al.,2005; Liu et al.,2007). Similar to other RTKs, forced homodimerization of Ror2 and stimulation with Wnt5a have been shown to enhance tyrosine kinase activity of Ror2, suggesting that Ror2 can transduce signals by mediating tyrosine phosphorylation of Ror2 by itself and its downstream substrates (Liu et al.,2007; Akbarzadeh et al.,2008; Liu et al.,2008).

Both Ror1 and Ror2 also possess the serine/threonine-rich domain (S/TRD1), proline-rich domain (PRD), and another serine/threonine-rich domain (S/TRD2) at the C-terminal to the TK domains (Masiakowski and Carroll,1992; Oishi et al.,1999; Yoda et al.,2003). Domains similar to the S/TRDs or PRDs of the Ror-family RTKs have not been found in any other proteins. The S/TRD1s of Ror1 and Ror2 show a higher degree of homology (∼67% identity), their PRDs show a relatively lower degree of homology (∼30% identity), but the S/TRD2s do not exhibit any apparent homology. These cytoplasmic domains are thought to be involved in the functions of the Ror-family RTKs by interacting with signaling mediators. Recently, it has been shown that Ror2 associates with the actin binding protein filamin A (FLNa) by means of its PRD, and this Ror2–FLNa interaction plays a mandatory role(s) in filopodia formation and Wnt5a-induced cell migration (Fig. 2; Nishita et al.,2006). Within these cytoplasmic domains, there are potential phosphorylation sites and several consensus motifs for protein interaction, such as the WW domain recognition motif, SH3 recognition motif, and SH2 recognition motif. These putative phosphorylation sites and motifs may contribute to the Ror2-mediated signal transduction by regulating association with adaptors and signaling molecules, containing WW, SH2, and/or SH3 domains.

DEVELOPMENTAL EXPRESSION OF THE ROR-FAMILY RTKS

Gene expression patterns of the Ror-family RTKs during development have been shown in mice, chicken, Xenopus, Drosophila, Aplysia, and C. elegans. In mice, embryonic expression patterns of Ror1 and Ror2 genes have been extensively studied (Oishi et al.,1999; Takeuchi et al.,2000; Al-Shawi et al.,2001; Matsuda et al.,2001; Kani et al.,2004). At the gastrulation stage, both Ror1 and Ror2 are expressed in the anterior part and primitive streak of embryos, respectively. Subsequently, expression of Ror1 is partly overlapped with that of Ror2, but tends to localize more restricted regions. At embryonic day (E) 8.5, both Ror1 and Ror2 transcripts are detected in the cephalic mesenchyme, predominantly in the cephalic neural crest cells. At E9.5–E10.5, Ror1 and Ror2 exhibit similar expression patterns in the craniofacial region, including frontonasal process and pharyngeal arches, that are originated from the cephalic neural crest. Specific expression of Ror1 is observed in the dorsal part of the diencephalons and mid–hind brain boundary, while that of Ror2 is found in the forebrain, midbrain, and presomitic mesoderm. Expressions of Ror1 and Ror2 are also at a higher level in the developing limbs, while their patterns are different. At E10.5, Ror1 transcripts are restricted to the proximal regions of limb buds, whereas Ror2 expression appears to extend throughout the limbs. Both of them are expressed in the limb mesenchyme, but not in the ectoderm. Ror1 expression in the limbs becomes restricted to the anterior and posterior regions (E12.5), and to the interdigital region (E13.5). Ror2 transcripts are detected in the perichondrium of the digits and the marginal regions of the limbs (E12.5–E13.5). At approximately E13.5 and a later stage, both Ror1 and Ror2 genes are observed in various tissues, including the heart, lung, kidney, gut, and nervous system. Specific expression of Ror1 is observed in the lens, terminal lamina of the hypothalamus, olfactory epithelium, aorta, aortic arch, and thymus. Ror2 expression is dominant in the telencephalon (especially in the limbic neocortex, hippocampal neuroepithelium, and caudate putamen), and dorsal root ganglia. These expression patterns suggest that Ror1 and Ror2 play important roles in the development of various tissues, and that they may have redundant and pleiotropic functions (see below). It is noteworthy that Wnt5a a ligand of Ror2 exhibits similar expression pattern in the early development of mice. Wnt5a is expressed in multiple tissues, including presomitic mesoderm, frontonasal process, pharyngeal arches, limb mesenchyme, and nervous system. These remarkably similar expression patterns of Ror2 and Wnt5a suggest that the interaction of these molecules regulates mammalian early development.

Embryonic expression patterns of chicken Ror1 (cRor1) and Ror2 (cRor2) have also been reported. Similar to mouse Rors, cRor1 and cRor2 are expressed in the developing limb. Expression of cRor1 is restricted to the proximal limb region until Hamburger and Hamilton stage (HH-stage) 25, and expands toward the distal region at later stages (Rodriguez-Niedenfuhr et al.,2004). In early limb buds (HH-stage 23), cRor2 expression is detected throughout the limb bud with a stronger expression in the anterior and posterior areas. At later stages, cRor2 expression in central mesenchyme of limb becomes weakened, while its expression in the anterior and posterior margins of limb stays prominent. cRor2 is also detected in several organs, including the nervous system, cartilage, muscles, mesonephros, heart, digestive system, lung, and liver (Stricker et al.,2006). These expression patterns of chicken Rors are essentially similar to those of mice.

In Xenopus, Ror2 (Xror2) transcripts are detected in the dorsal mesoderm and ectoderm of a gastrula stage embryo, then found in the notochord, neuroectoderm, and neural crest in late gastrula to neurula embryos. The expression of Xror2 is restricted to the pharyngeal arches in tail bud stage embryos (Hikasa et al.,2002). Consistent with the early expression pattern of Xror2, loss of function of Xror2 results in the defect of convergent extension (CE) movements (Schambony and Wedlich,2007).

In Aplysia and Drosophila, Ror genes are detected in the developing nervous system, but not in other tissues (Wilson et al.,1993; Oishi et al.,1997; McKay et al.,2001b). The function of the Ror-family RTKs in these organisms are still unknown, but their specific expression patterns suggest their functions in the development of the nervous system.

Gene expression analyses revealed that C. elegans ortholog of Ror2, cam-1, is expressed in the nervous system, intestinal cells, hypodermal cells, muscles in the head, pharynx, and body wall, and vulval precursor cells (Forrester et al.,1999; Koga et al.,1999; Francis et al.,2005; Green et al.,2007). Consistent with its expression patterns, cam-1 plays crucial roles in neuronal migration, neuronal development, asymmetric cell divisions, and in valval development.

In human, expression of neither Ror1 nor Ror2 genes have been characterized. In silico analyses of human expressed sequence tags suggest that Ror1 is expressed in embryonic stem cells, infant brain, renal cancer, and colon cancer, and that Ror2 is expressed in the parathyroid, testis, uterus, and diffuse-type gastric cancer with signet ring cell features (Katoh,2005).

DEVELOPMENTAL FUNCTIONS OF THE ROR-FAMILY RTK(S) IN C. ELEGANS AND X. LAEVIS

C. elegans

Developmental functions of C. elegans ortholog of the Ror-family RTKs, CAM-1 have been reported in studies of C. elegans mutants with defects in the directed migrations of several neurons along the anterior–posterior (A-P) axis. (Forrester and Garriga,1997; Forrester et al.,1999). For example, canal-associated neurons (CANs) and anterior lateral microtubule (ALM) neurons, migrating posteriorly to positions near the middle of the embryo, terminate prematurely on the way to proper positions in cam-1 mutants, whereas hermaphrodite-specific neurons (HSNs) and BDU neurons migrate anteriorly beyond their normal destination in the mutants. In addition to the migration defects, cam-1 mutants display defects in asymmetric cell divisions of hypodermal V1 cells and Pn.aap neuroblasts, and axon outgrowth (Forrester and Garriga,1997; Forrester et al.,1999). Interestingly, all these defects are observed in cam-1(gm122) mutants, which have a nonsense mutation within the extracellular CRD domain of CAM-1, whereas only limited defects are observed in cam-1(gm105) mutants, which have a mutation that is predicted to produce a protein lacking the TK domain, suggesting that kinase activity is dispensable for at least some CAM-1 functions. This possibility is further supported by the observation that a transgene encoding a form of cam-1 in which a conserved lysine within the kinase domain is altered to arginine, a change that is predicted to abolish its kinase activity, rescues the cell migration defects in cam-1(gm122) mutants (Forrester et al.,1999).

Functional analyses of the structural domains of CAM-1, including Ig-like, CRD, Kringle, TK, and S/TRDs, have revealed that the CRD, but not other domains, is required for the proper migrations of CAN, ALM, HSN, and BDU neurons (Kim and Forrester,2003). However, it has been shown that several CAM-1 functions require the TK domain, that is, disrupted polarity of asymmetric cell divisions of Pn.aap neuroblasts can be seen in cam-1(gm105) mutants (Forrester et al.,1999), and cam-1(ks52) mutants, which have a deletion in the TK domain of CAM-1, show constitutive dauer larva formation (Koga et al.,1999).

In addition to the defects of cam-1 mutants in cell migration and cell polarity, cam-1 mutants has been reported to have defects in synaptic transmission at the neuromuscular junction (NMJ; Francis et al.,2005). The defects at the NMJ appear to arise as consequences of mislocalizations of an acetylcholine receptor subunit at postsynaptic sites and of synaptic vesicles at presynaptic sites.

It has been shown that CAM-1 negatively regulates Wnt signaling. Mutations in egl-20, a C. elegans Wnt, suppress the overmigration of HSNs in cam-1 mutants, and overexpression of EGL-20, like cam-1 mutations, causes anterior displacement of the HSNs (Forrester et al.,2004). The findings propose a model that CAM-1 sequesters Egl-20 possibly by means of direct binding of CAM-1 CRD with EGL-20. The sequestration model is further supported by a study of CAM-1 function in the development of vulva (Green et al.,2007). The C. elegans vulva is formed from the reproducible divisions of vulva precursor cells (VPCs) arranged along the A-P axis in the ventral epithelium. It has been shown that overexpression of CAM-1 can inhibit vulval induction mediated by Wnt in a non–cell-autonomous manner, and the extracellular CRD of CAM-1 binds to several C. elegans Wnts, including EGL-20. It has recently been reported that EGL-20/CAM-1 signaling contributes to establish the proper arrangement of VPCs mediated by polarized cell divisions in vulval formation by means of the intracellular domain of CAM-1 (Green et al.,2008a). These findings suggest that the function of CAM-1 is not only regulated by the Wnt-binding extracellular domain, but also by the intracellular domain, which contributes to a cell-autonomous action.

X. laevis

It has been demonstrated that Xror2, Xenopus ortholog of the mammalian Ror2, plays crucial roles in CE morphogenetic movements and neural plate closure. Xror2 was initially isolated as a gene whose expression is up-regulated by the organizer-specific LIM homeobox gene, Xlim-1 (Hikasa et al.,2002). Ectopic expression of Xror2 causes disruption of CE during gastrulation and affects neural plate closure during neurulation, although it fails to induce secondary axis that Xlim-1 can induce. In accordance with the phenotype observed in C. elegans cam-1 mutants, that is, defects in cell migration and asymmetric cell division, Xror2 appears to regulate partly CE irrespective of its cytoplasmic region, because the expression of Xror2 mutant lacking the cytoplasmic domain can also inhibit CE (Hikasa et al.,2002).

Xenopus Wnt5a (Xwnt5a) has been shown to regulate CE movements during Xenopus development (Moon et al.,1993; Yamanaka et al.,2002). Mammalian Ror2 is capable of binding to mammalian Wnt5a by means of its CRD, and coexpression of Wnt5a and Ror2 synergistically inhibited CE, indicating that Wnt5a and Ror2 interact functionally to regulate CE (Oishi et al.,2003). Recently, Xwnt5a/Xror2 signaling has been shown to regulate the transcription of paraxial protocadherin (XPAPC) in the regulation of CE movements in Xenopus gastrulation (Schambony and Wedlich,2007). Suppressed expression of Xwnt5a, Xror2, or XPAPC similarly results in disrupted mediolateral orientation and randomized movements of cells in Keller open-face explants, indicating that Xwnt5a/Xror2 signaling regulates CE by controlling polarized cell movements. Furthermore, Xwnt5a/Xror2-mediated XPAPC transcription appears to require the kinase activity of Xror2, indicating that both kinase domain-dependent and -independent functions of Xror2 are involved in the regulation of CE during Xenopus gastrulation.

DEVELOPMENTAL FUNCTIONS OF WNT5A, ROR1, AND ROR2 IN MAMMALS

Wnt5a Mutant Mice

Mice lacking Wnt5a gene was originally generated by Yamaguchi et al. (1999) and extensive studies have been done using the mutant mice to elucidate the roles of Wnt5a in the development of various organs and tissues (Table 1). Wnt5a mutant mice show dwarfism, facial anomalies, short limbs and tails, and respiratory dysfunction, leading to perinatal or neonatal lethality (Yamaguchi et al.,1999; Oishi et al.,2003; see Table 1). The mutant mice show the outgrowth defects of multiple structures, including the limbs, face, ears, and genitals, whose development requires extension from the main body axis, reflecting the findings that Wnt5a is expressed in a graded manner in the developing limb, face, and genitals. Their fore- and hindlimbs are extensively shortened and lack digits, and their ribs and vertebrae are often fused. They also exhibit hypoplasia of the snout, mandible, and tongue, and external genitalia agenesis (Yamaguchi et al.,1999; Oishi et al.,2003; Suzuki et al.,2003). Wnt5a is also expressed in a graded manner along the A-P axis of the developing palate, and a complete cleft of the secondary palate is seen in Wnt5a mutant mice, due to altered cell migration in the palatal mesenchyme (He et al.,2008).

Table 1. Phenotypes of Wnt5a, Ror1, Ror2, and Ror1/Ror2 Mutant Mice

	Wnt5a KO	Ror1 KO	Ror2 KO	Ror1/Ror2 KO	Reference
(1) neonatal lethality	+	+	+	+	Oishi et al.,2003
(2) forced respiration and cyanosis	+	+	+	+	Oishi et al.,2003
(3) respiratory dysfunction	+	+	+	+	Oishi et al.,2003
(4) skeletal phenotypes
a) facial anomalies	++	−	+	++	Yamaguchi et al.,1999; Nomi et al.,2001; Oishi et al.,2003
b) hypoplasia of the maxilla and mandible	++	−	+	++	Yamaguchi et al.,1999; Nomi et al.,2001; Oishi et al.,2003
c) cleft palate	+	−	+	N.D.	He et al.,2008
d) short limbs and tail	++	−	+	++	Yamaguchi et al.,1999; Nomi et al.,2001; Oishi et al.,2003
e) dysplasia of the proximal long bones	++	−	+	++	Yamaguchi et al.,1999; Nomi et al.,2001; Oishi et al.,2003
f) dysplasia of the distal long bones	+	−	+	+	Yamaguchi et al.,1999; Nomi et al.,2001; Oishi et al.,2003
g) sternal defect	N.D.	−	−	+	Nomi et al.,2001
h) dysplasia of symphysis of the public bone	N.D.	−	−	+	Nomi et al.,2001
i) bone loss (decreased trabecular bone mass)	+	N.D.	N.D.	N.D.	Takada et al.,2007
(5) bone marrow phenotype
enhanced adipogenesis	+	N.D.	N.D.	N.D.	Takada et al.,2007
(6) cardiac phenotypes
a) ventricular septal defect (VSD)	+	−	+	+	Takeuchi et al.,2000; Oishi et al.,2003
b) persistent truncus arteriosus (PTA)	+	−	+	N.D..	Nomi et al.,2001; Schleiffarth et al.,2007
c) transposition of the great arteries	+	−	−	+	Nomi et al.,2001; Oishi et al.,2003
(7) lung phenotype
truncation of trachea and abnormalities in distal lung architecture	++	−	+	++	Li et al.,2002
(8) intestinal phenotype
shortening of the small intestine and aberrant bifurcation of the midgut	+	N.D.	N.D.	N.D.	Cervantes et al.,2009
(9) pancreatic phenotype
insulin-cell migration	+	N.D.	N.D.	N.D.	Kim et al.,2005
(10) genital phenotype
a) outgrowth defects in the genitals	+++	−	+	++	Yamaguchi et al.,1999; Oishi et al.,2003; Suzuki et al.,2003
b) defects in FRT development	+	N.D.	N.D.	N.D.	Mericskay et al.,2004
(11) PCP/CE defect in cochlea	+	N.D.	+	N.D.	Qian et al.,2007; Yamamoto et al.,2008

Significant phenotypes are also observed in various organs and tissues of Wnt5a mutant mice (Table 1). Wnt5a is expressed in the mouse lung, and Wnt5a mutant mice exhibit truncation of the trachea and abnormalities in distal lung architecture, characterized by overexpansion of the distal airways and inhibition of lung maturation without affecting differentiation of pulmonary cell types (Li et al.,2002). The cardiac anomalies, including the ventricular septal defects (VSD) and complete transposition of the great arteries, are found in Wnt5a mutant mice (Oishi et al.,2003). In addition, they show persistent truncus arteriosus (PTA), resulting from lack of septation of the cardiac outflow tract (Schleiffarth et al.,2007). Wnt5a is also expressed in the gut mesenchyme during intestinal development, and Wnt5a mutant mice display drastically shortened small intestine with an aberrant bifurcation of the midgut (Cervantes et al.,2009), suggesting an essential role of Wnt5a in the development and elongation of the small intestine from the midgut region. Interestingly, the roles of Wnt5a in the development of the pancreas and female reproductive tract (FRT) have also been reported (Mericskay et al.,2004; Kim et al.,2005). Although the size and morphology of the pancreas in Wnt5a mutant mice are rather normal, they show the defect of the insulin-positive cell migration from the pancreatic ducts (Kim et al.,2005). The posterior Müllerian-derived structures (cervix and vagina) were absent in Wnt5a mutant mice, while the anterior Müllerian-derived structures (oviducts and uterine horns) can easily be identified in them (Mericskay et al.,2004).

Previous studies using fly, frog, and zebrafish have shown that loss and gain of Wnt5a function results in dysregulated CE movements and planar cell polarity (PCP) during developmental morphogenesis (Moon et al.,1993; Mlodzik,2002; Kilian et al.,2003). Both PCP and CE movements can be seen during the development of the cochlea. Importantly, Wnt5a mutant mice have misoriented stereocilia and cochlear phenotypes (a shortened and widened cochlea) (Qian et al.,2007, see Table 1), indicating that Wnt5a is indeed required for proper PCP and CE movements during cochlear development, characteristic features of noncanonical Wnt signaling. Intriguingly, recent study with Wnt5a^+/− mice has shown that Wnt5a potentiates the cell-lineage decision of bone marrow mesenchymal progenitors into osteoblasts (Takada et al.,2007). In fact, compared with wild-type mice, Wnt5a^+/− mice show a clear bone-loss phenotype, with decreased trabecular bone mass and increased number of adipocytes in bone marrow.

Ror1 and Ror2 Mutant Mice

Like Wnt5a mutant mice, Ror2 mutant mice show dwarfism, facial anomalies, short limbs and tails, and respiratory dysfunction, leading to neonatal lethality (DeChiara et al.,2000; Takeuchi et al.,2000; see Table 1). Although Ror2 mutant mice exhibit several skeletal phenotypes, that is, short limbs and tail, abnormal vertebrae, fusion of ribs, and abnormal facial structures, somewhat similar to those of Wnt5a mutant mice, their defects are more severe in the more distal portions (DeChiara et al.,2000; Takeuchi et al.,2000). Ror2 mutant mice also display a unique anomaly characterized by mesomelic dysplasia (significant or complete loss of the radius, ulna, tibia, and fibula). Like Wnt5a mutant mice, it has been shown that Ror2 mutant mice also exhibit a cleft palate, and that Wnt5a^+/−; Ror2^+/− mice show cleft palate defects resembling that of Ror2^−/− mice (He et al.,2008). Ror2 mutant mice show abnormalities in their lungs with foreshortened trachea along with the proximal–distal axis and a reduced number of cartilage rings, similar to Wnt5a mutant mice (Oishi et al.,2003). They also exhibit outgrowth defects in the genitals, yet their genital hypoplasia is somewhat modest compared with Wnt5a mutant mice (Oishi et al.,2003). Ror2 mutant mice have VSD and PTA (Table 1) without any other abnormalities in the heart, i.e., malformation of valves, aortic arch, and great vessels (Takeuchi et al.,2000). In addition to these similarities in phenotypes of Ror2 mutant mice with those of Wnt5a mutant mice, misoriented stereocilia and cochlear phenotypes are also found in Ror2 mutant mice, indicating that PCP and CE movements are also dysregulated in Ror2 mutant mice (Yamamoto et al.,2008). Overall similarities in phenotypes of Ror2 mutant mice with those of Wnt5a mutant mice strongly implicate an overlapping role for Wnt5a and Ror2 (Table 1). In fact, it has been well documented that Ror2 acts as a receptor or coreceptor for Wnt5a (see below).

In contrast with Ror2 mutant mice, Ror1 mutant mice are similar in size to wild-type mice and do not show any apparent morphological abnormalities, yet they usually die neonatally due to respiratory dysfunction and cyanosis, like Wnt5a and Ror2 mutant mice (Nomi et al.,2001). Although histological examination of the lungs from Ror1 mutant mice reveals that expansion of the alveoli in the mutant mice is incomplete, they do not show any morphological abnormalities in their lungs. Because Ror1 and Ror2 genes show similar expression patterns in the developing face, limbs, heart, and lungs (Matsuda et al.,2001), the lack of apparent morphological abnormalities in Ror1 mutant mice can be explained by functional redundancy between Ror1 and Ror2. It has been shown that Ror1 indeed interacts genetically with Ror2 during developmental morphogenesis (Nomi et al.,2001). Ror1 and Ror2-double mutant mice (Ror1/Ror2 mutant mice) exhibit perinatal lethality, and in fact they usually die before their delivery. Gross appearances of Ror1/Ror2 mutant mice exhibit enhanced Ror2 mutant phenotypes (Table 1). The shortening of limb and tail length in proportion to body length and malformation of the facial structures observed in Ror2 mutant mice are more profound in Ror1/Ror2 mutant mice. Ror1/Ror2 mutant mice show a drastic enhancement of the skeletal abnormalities observed in Ror2 mutant mice. Interestingly, dysplasia of the proximal long bones, in addition to dysplasia of the distal long bones, is also observed in Ror1/Ror2 mutant mice, like Wnt5a mutant mice (Table 1). Of interest, Ror1/Ror2 mutant mice exhibit a sternal defect (sternal agenesis) and dysplasia of the symphysis of the pubic bone, skeletal abnormalities that are not seen in Ror2 mutant mice (Nomi et al.,2001). Moreover, in addition to VSD and PTA, Ror1/Ror2 mutant mice show complete transposition of the great arteries, a phenotype observed in Wnt5a mutant mice but not in Ror2 mutant ones (Table 1). Collectively, these findings confirm that Ror1 and Ror2 interact genetically in regulating the development of the skeletal and cardiovascular systems.

ROLES OF WNT5A, ROR1, AND ROR2 IN HUMAN DISEASES

Ror2 and Genetic Skeletal Diseases

Consistent with the findings that Ror2 plays essential roles in the regulation of developmental morphogenesis of various organs and tissues (see above), in humans, mutations within Ror2 gene cause autosomal dominant brachydactyly type B (BDB), the most severe of the brachydactylies characterized by hypoplasia/aplasia of distal phalanges and nails (Oldridge et al.,2000; Schwabe et al.,2004), and autosomal recessive form of Robinow syndrome (RRS), characterized by mesomelic shortening, abnormal morphogenesis of the face (fetal facies), hemivertebrae, and genital hypoplasia (Afzal et al.,2000; van Bokhoven et al.,2000; reviewed in Patton and Afzal,2002; Afzal and Jeffery,2003). All of the reported mutations in BDB cause truncation of the predicted Ror2 protein before and after the TK domain within its cytoplasmic portion, indicating dominant-negative functions of mutant Ror2 proteins. Some of the mutations in BDB patients not only cause truncation of the protein, but also produce a novel C-terminal polypeptide (reviewed in Afzal and Jeffery,2003), raising a question of the possible significance of the novel C-terminal peptides in BDB. Ror2^W749X, resulting from a 2246G to A substitution mapping downstream of the TK domain, is linked to BDB in humans. Of interest, although mice heterozygous for Ror2^W749FLAG (the mutation of W749X is introduced into the mouse Ror2 gene) are normal and do not show brachydactyly, homozygous mice exhibit phenotypes resembling human RRS (Raz et al.,2008).

In contrast to BDB, RRS is caused by different homozygous missense, nonsense, and frameshift mutations within Ror2 gene, indicating loss-of-function effects of mutant Ror2 proteins. Consistent with this observation, it has been appreciated that Ror2 mutant mice (Ror2^−/− mice) can be a model for the developmental pathology of RRS in humans (Schwabe et al.,2004). Ror2 mutations found in RRS can be divided into two groups, that is, the first bearing missense mutations in the CRD, Kringle, and TK domains, and the second bearing nonsense mutations, resulting in truncation at C-terminal to the CRD domain (reviewed in Afzal and Jeffery,2003). It has been reported that all the missense mutations within Ror2 gene causing RRS are retained in the endoplasmic reticulum (ER) presumably due to improper folding of mutant Ror2 proteins and subjected to ER-associated degradation (Chen et al.,2005; Ali et al.,2007). Further study will be required to clarify molecular pathology of RRS. In comparison with BDB, the range of severity in RRS is broad. Clinical and molecular examinations of two adults with RRS identify nephrological abnormalities (hydronephrosis, nephrocalcinosis, and renal failure) and endocrinological abnormalities (elevated gonadotropic hormones), respectively (Tufan et al.,2005). In addition, patients with RRS caused by a novel intragenic Ror2 deletion, involving exons 6 and 7, exhibit cleft lip, cleft palate, and cardiac anomalies, and one patient has syringomyelia as well (Brunetti-Pierri et al.,2008).

Wnt5a, Ror1, Ror2, and Malignancies

Wnt-family proteins can be classified into three distinct types of transforming ability. The highly transforming members include Wnt1, Wnt3a, and Wnt7a; the intermediately transforming members include Wnt2, Wnt5b, and Wnt7b; and nontransforming members include Wnt4, Wnt5a, and Wnt7b (Jue et al.,1992; Wong et al.,1994). Because Wnt5a has also been shown to inhibit β-catenin–dependent canonical Wnt signaling that is often activated in tumor cells, it can be assumed that Wnt5a may act as a tumor suppressor. In fact, it has been reported that antisense Wnt5a mimics Wnt1-mediated transformation of mouse mammary epithelial cells (Olson and Gibo,1998), and haploinsufficiency of Wnt5a is associated with the development of B cell lymphoma in mice (Liang et al.,2003). Clinical and/or molecular analyses of primary invasive breast carcinoma and neuroblastoma also reveal that loss and/or low expression of Wnt5a are associated with aggressiveness of these carcinomas (Jönsson et al.,2002; Blanc et al.,2005). Furthermore, Wnt5a has been shown to inhibit cell growth, migration, and invasiveness of thyroid cancer cells and colorectal cancer cells (Dejmek et al.,2005; Kremenevskaja et al.,2005; see Table 2), supporting the above notion. However, there are several lines of evidence indicating that increased or sustained expression of Wnt5a is critically involved in various types of cancer or cancer cell line, including prostate cancer, gastric cancer, melanoma, breast cancer cell line, and osteosarcoma cell lines (Iozzo et al.,1995; Weeraratna et al.,2002; Kurayoshi et al.,2006; Pukrop et al.,2006; Enomoto et al.,2009, in press; see Table 2). Therefore, the roles of Wnt5a in human cancers are currently controversial (see Table 2), although it is conceivable that the discrepancy reflects differences in receptor context or cell context of cancer cells.

Table 2. Possible Roles of Wnt5a, Ror1, and Ror2 in Human Malignancies

	Type of cancer	Role	Reference
Wnt5a	gastric cancer	oncogenic	Kurayoshi et al.,2006
	colon cancer	anti-oncogenic	Dejmek et al.,2005
	thyroid carcinoma	anti-oncogenic	Kremenevskaja et al.,2005
	ductal breast carcinoma	anti-oncogenic	Jönsson et al.,2002
	breast cancer cell line (MCF-7 cells)	oncogenic	Pukrop et al.,2006
	neuroblastoma	anti-oncogenic	Blanc et al.,2005
	melanoma	oncogenic	Weeraratna et al.,2002
	osteosarcoma	oncogenic	Enomoto et al.,2009 (in press)
	prostate carcinoma	oncogenic(?)	Iozzo et al.,1995
	B-cell lymphoma	anti-oncogenic	Liang et al.,2003
Ror1	chronic lymphocytic leukemia (CLL)	oncogenic	Baskar et al.,2008; Daneshmanesh et al.,2008; Fukuda et al.,2008
	acute lymphoblastic leukemia (ALL)	oncogenic	Shabani et al.,2007
Ror2	squamous cell carcinoma	oncogenic	Kobayashi et al.,2009
	osteosarcoma	oncogenic	Enomoto et al.,2009 (in press)

Studies examining the possible roles of Ror2, a receptor or coreceptor for Wnt5a, in human cancers are now under way. It has recently been reported that increased expression of Ror2 is observed in squamous cell carcinoma of the oral cavity, and that high expression of Ror2 is associated with the degree of malignancy (Kobayashi et al.,2009; see Table 2). More recently, it has been shown that osteosarcoma cell lines SaOS-2 and U2OS exhibit invasive properties in vitro by activating noncanonical Wnt5a/Ror2 signaling in a cell-autonomous manner (Enomoto et al.,2009, in press; see Table 2). In fact, invasiveness of these cells can be inhibited by suppressed expression of either Ror2 or Wnt5a (see below). Further study will be required to clarify the roles of Wnt5a/Ror2 signaling in human cancers. On the other hand, several lines of evidence indicate that high or overexpression of Ror1 is critically involved in hematopoietic malignancies of B-cell lineage in humans (Shabani et al.,2007; Baskar et al.,2008; Daneshmanesh et al.,2008; Fukuda et al.,2008; see Table 2).

THE ROR-FAMILY RTKS AS A RECEPTOR(S) FOR WNT5A

Functions of Wnt5a/Ror2 Signaling in Polarized Cell Migration

As described above, physical and functional interaction of Ror2 and Wnt5a have been reported in many studies using mice, Xenopus, culture cells, and in vitro systems. Thus, Ror2 is regarded as a receptor or coreceptor for Wnt5a, mediating noncanonical Wnt signaling. PCP and CE defects in Ror2-deficient mouse embryos and abnormal cell polarity and movement in C. elegans cam-1 mutants suggest that Ror2 mediates Wnt5a signaling to regulate polarized cell migration. In fact, transwell migration assay revealed that Wnt5a induces cell migration of mouse embryonic fibroblasts (MEFs) from wild-type but not Ror2-deficient mice (Nishita et al.,2006). In contrast, Wnt3a stimulation induces significant cell migration of both wild-type and Ror2-deficient MEFs at almost comparable levels (Nishita et al.,2006). These results indicate that Ror2 is required for Wnt5a-induced cell migration of MEFs.

An in vitro wound-healing assay has also been used to study Wnt5a-induced polarized cell migration. Wnt5a stimulates closure of wounded-monolayer of NIH3T3 cells, expressing Ror2 endogenously by inducing lamellipodia formation and MTOC reorientation of wound-edge cells (Nomachi et al.,2008). In fact, these cellular events can be impaired by suppressed expression of Ror2. JNK is activated at the wound edge, in a Ror2-dependent manner, following Wnt5a stimulation, and inhibition of JNK activity abrogates Wnt5a-induced lamellipodia formation and MTOC reorientation. Moreover, Wnt5a-induced JNK activation and MTOC reorientation can be suppressed by inhibiting aPKC (PKCζ), suggesting a possible functional link between Wnt5a/Ror2/JNK and Par/aPKC pathways in polarized cell migration (Fig. 2). It is unclear about the mechanisms by which aPKC regulates JNK activity in Wnt5a signaling. However, it has recently been reported that aPKC associates with Dishevelled (Dvl), a key component of PCP pathway functioning upstream of JNK, and that Dvl is required for Wnt5a-induced cell migration (Fig. 2; Nishita et al.,2006; Schlessinger et al.,2007), raising the possibility that aPKC might regulate Wnt5a-induced JNK activation through Dvl in wound-healing cells. The role of Wnt5a/Ror2 in polarized cell migration has also been studied using in vitro organ culture of developing palate, in which Wnt5a acts as a chemoattractant for palatal mesenchymal cells by means of Ror2-mediated noncanonical pathway (He et al.,2008).

Wnt5a/Ror2 Signaling and Tumor Invasion/Progression

Sustained or increased Wnt5a expression is critically involved in invasion or progression of various types of cancer (Iozzo et al.,1995; Weeraratna et al.,2002; Kurayoshi et al.,2006; Pukrop et al.,2006). The role of Ror2 in tumor invasion has been studied using the human osteosarcoma cell lines SaOS-2 and U2OS cells (Enomoto et al.,2009, in press). Endogenous expression of both Wnt5a and Ror2 on these cells confers invasive properties by activating Wnt5a/Ror2 signaling in a cell-autonomous manner. In fact, suppressed expression of Wnt5a or Ror2 in these osteosarcoma cells inhibits cell invasiveness accompanying decreased invadopodia formation and extracellular matrix (ECM) degradation without affecting proliferation and cell attachment to ECM. Importantly, activation of a Src-family protein tyrosine kinase (SFK)(s) is critically involved in Wnt5a/Ror2-induced invasiveness, by inducing matrix metalloproteinase 13 (MMP-13) gene expression, which is essential for ECM degradation of osteosarcoma cells (Fig. 3). It is unclear whether Ror2 also contributes to the invasiveness of other types of tumors.

Regulation of Canonical Wnt Signaling by Ror2

Wnt5a/Ror2 signaling plays a crucial role in inhibiting canonical Wnt signaling at the level of TCF/LEF-mediated transcription (Mikels and Nusse,2006; Li et al.,2008). In fact, Wnt5a inhibits Wnt3a-induced expression of the TCF/LEF-driven reporter gene in a Ror2-dependent manner. Furthermore, suppressed expression of either Ror2 or Wnt5a in SaOS2 cells results in the enhancement of the reporter gene expression without affecting β-catenin levels (Enomoto et al.,2009, in press), indicating that Wnt5a/Ror2 signaling is constitutively activated in SaOS-2 cells, thereby inhibiting TCF/LEF-mediated transcription. In contrast, Ror2 can potentiate Wnt1- or Wnt3a-induced reporter gene expression (Billiard et al.,2005; Green et al.,2008b; Li et al.,2008). Thus, Ror2 can inhibit or activate TCF/LEF-mediated transcription depending on which Wnt is present. It is also possible that specificity of Ror2-mediated signaling pathways is conferred by other Wnt receptors, like Fzds, or cofactors that form complexes with Ror2 on cell surface, such as collagen triple helix repeat containing 1 (Cthrc1), a secreted glycoprotein that binds to Wnts, Fzds, and Ror2, and activates the PCP pathway selectively by stabilizing the Wnt-receptor complex (Yamamoto et al.,2008).

Ror1 and Hematopoietic Malignancies

Recent molecular investigations have demonstrated that overexpression of a set of tumor-associated antigens can be correlated with malignancies. Overexpression of Ror1 has recently been reported in B-cell chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) (Shabani et al.,2007; Baskar et al.,2008; Daneshmanesh et al.,2008; Fukuda et al.,2008; Shabani et al.,2008). Ror1 and Wnt5a can physically interact and cooperatively activate NF-κB when overexpressed in HEK293 cells (Fukuda et al.,2008). Wnt5a enhances the survival of CLL cells in vitro, an effect that could be neutralized by anti-ROR1 antisera. These findings suggest that Ror1 functions as an oncofetal surface antigen through which Wnt5a activates NF-κB–dependent survival signaling in CLL. In agreement with this, Ror1 was identified as a prosurvival kinase in HeLa cervical carcinoma cells (MacKeigan et al.,2005).

MOLECULAR MECHANISMS OF NONCANONICAL WNT SIGNALING MEDIATED BY ROR2

Structure–Function Relationship of Ror2

Roles of the kinase activity or the respective structural domains of Ror2 in Wnt5a-induced cell migration have been studied by using a mouse fibroblastic cell line, L cells in which endogenous expression of Ror2 is undetectable (Nishita et al.,2006). Because the CRD of Ror2 is a binding domain for Wnt5a, expression of Ror2 mutant, lacking the CRD, in L cells fails to mediate Wnt5a-induced migration, indicating that binding of Wnt5a to Ror2 is essential. Interestingly, L cells expressing kinase-inactive Ror2 mutant exhibit enhanced cell motility following Wnt5a stimulation at similar extents as L cells expressing wild-type Ror2 do. Thus, kinase activity of Ror2 is dispensable for Wnt5a-induced cell migration. In contrast, the cytoplasmic C-terminal portion of Ror2, containing the PRD and S/TRD2, is essential for Wnt5a-induced cell migration. Importantly, yeast two hybrid screening identified an actin binding protein filamin A (FLNa) as a binding partner for the C-terminal portion of Ror2 (Fig. 2; Nishita et al.,2006). The Ror2-FLNa interaction is crucial for Ror2-induced filopodia formation and Wnt5a-induced polarized cell migration. FLNa might regulate Wnt5a-induced polarized cell migration by directly rearranging the actin cytoskeleton to form membrane protrusions (filopodia and lamellipodia), required for cell polarization and migration. In addition to its role in actin rearrangements, FLNa is also known to function as a scaffold protein in various signal transduction pathways (Stossel et al.,2001). In fact, the Ror2-FLNa interaction seems to be essential for Wnt5a-induced JNK activation (Fig. 2; Nomachi et al.,2008), suggesting the role of FLNa as a scaffold in Wnt5a/Ror2/JNK signaling, where Ror2 and its downstream molecule(s), mediating JNK activation, could be tethered to FLNa. In this respect, it is important to note that SEK/MKK4, an upstream activator of JNK, associates with FLNa (Marti et al.,1997). More recently, O'Connell et al. has reported that Wnt5a/Ror2 signaling induces FLNa cleavage by calpain-1 to stimulate cell motility in melanoma cells (O'Connell et al.,2009). It is of interest to study whether FLNa cleavage is involved in Wnt5a/Ror2/JNK signaling.

The kinase-dependent function of Ror2 in Wnt5a signaling has also been reported. In U2OS osteosarcoma cells, Wnt5a induces homodimerization and tyrosine phosphorylation of Ror2 (Liu et al.,2008). Ror2 has been shown to associate directly with and phosphorylates 14-3-3β, a scaffold protein that negatively regulates osteogenesis per se (Liu et al.,2007). Furthermore, Wnt5a stimulation induces phosphorylation of 14-3-3β (Liu et al.,2008), leading to a notion that Wnt5a/Ror2 signaling promotes osteogenesis by preventing the 14-3-3β–mediated inhibition by means of phosphorylation. In T/C-28a2 chondrocytes, Wnt5a induces Ror2 phosphorylation by Src through a mechanism that requires the PRD and S/TRD1 of Ror2 (Akbarzadeh et al.,2008). Interestingly, intrinsic kinase activities of both Src and Ror2 are required for Wnt5a- induced internalization of Ror2 into Rab5A-positive endosomes. From these results, a model of Ror2 activation has been proposed, i.e., through its intrinsic kinase activity, Ror2 recruits and activates Src, which in turn enhances phosphorylation of Ror2 by Src, resulting in a full-scale activation of Ror2. Furthermore, it has recently been found that Wnt5a stimulation of SaOS2 osteosarcoma cells also induces activation of SFKs, which is responsible for MMP-13 induction and invadopodia formation (Fig. 3; Enomoto et al.,2009, in press). Furthermore, the intrinsic kinase activity of Ror2 is indispensable for invadopodia formation of SaOS2 cells (Enomoto et al.,2009, in press). Thus, the kinase activity of Ror2 seems to play important roles in some aspects of Wnt5a/Ror2 signaling-mediated cellular functions depending on cellular contexts.

Downstream Targets of Wnt5a/Ror2 Signaling

As mentioned above, Wnt5a/Ror2 signaling regulates MTOC reorientation of wound-healing cells by means of JNK (Nomachi et al.,2008). Despite the fact that increased phosphorylation of c-Jun transcription factor by JNK can be detected in wound-healing cells stimulated with Wnt5a, treatment of the cells with actinomycin D, an inhibitor of transcription, fails to exert any apparent effects on Wnt5a-induced MTOC reorientation (Nomachi et al.,2008), indicating that gene expression is not required, at least for Wnt5a-induced MTOC reorientation. On the other hand, in Xenopus embryos Wnt5a/Ror2/JNK signaling up-regulates expression of the paraxial protocadherin XPAPC gene by means of c-Jun and ATF2 transcription factors (Schambony and Wedlich,2007). Induction of XPAPC is required for CE movements during gastrulation of Xenopus embryos. Treatment with cycloheximide, an inhibitor of protein synthesis, fails to suppress XPAPC induction by Wnt5a, suggesting a direct regulation of XPAPC gene expression by Wnt5a/Ror2/JNK signaling through c-Jun/ATF2.

Another target gene, known to be regulated by Wnt5a/Ror2 signaling, is MMP-13. Suppressed expression of either Ror2 or Wnt5a results in inhibition of MMP-13 expression in SaOS2 cells, and conversely, stimulation of serum-starved SaOS2 cells with Wnt5a leads to induction of MMP-13 (Enomoto et al.,2009, in press). Expression of MMP-13 by Wnt5a/Ror2 signaling can be abrogated by an inhibitor of the SFKs, suggesting the role of the SFK(s) in MMP-13 expression by means of Wnt5a/Ror2 signaling (Fig. 3). At present, it is unclear whether JNK is also involved in MMP-13 expression by Wnt5a/Ror2 signaling. With this respect, it is worth noting that suppressed expression of Ror2 results in decreased phosphorylation of c-Jun in SaOS2 cells (Enomoto et al.,2009, submitted). Furthermore, the promoter region within MMP-13 gene contains an AP-1 site, a c-Jun/c-Fos responsive element, and induction of MMP-13 gene by extracellular stimuli, such as IL-1β and TGF-β, is mediated at least partly by this AP-1 site (Pendas et al.,1997; Uria et al.,1998). These findings raise the possibility that Wnt5a/Ror2/Src signaling may target directly the MMP-13 promoter by means of JNK/c-Jun.

The calcium-sensing receptor (CaSR) is a G-protein coupled receptor, which senses extracellular levels of Ca²⁺. It has been reported that activation of CaSR in colonic myofibroblast cells and colon carcinoma cells results in induced expression of Wnt5a and Ror2, respectively, which potentiates Wnt5a/Ror2 signaling in the colon carcinoma cells (Pacheco and Macleod,2008). Activation of Wnt5a/Ror2 signaling in the colon carcinoma cells increases expression of CDX2, an intestinal-specific homeobox domain transcription factor known to play a critical role in the differentiation and maintenance of intestinal epithelial functions. Because Ca²⁺ is a chemoprotective agent for colon cancer, these results suggest that Wnt5a/Ror2 signaling may regulate calcium-mediated chemoprevention of colon cancer by inducing CDX2 expression. With this respect, it is worth noting that reduced levels of CDX2 in Cdx2^+/− mice result in increased colon tumor progression (Aoki et al.,2003; Bonhomme et al.,2003).

Possible Candidate Molecules Involved in Wnt5a/Ror2 Signaling

Ror2 associates with the melanoma-associated antigen family protein Dlxin-1 by means of the C-terminal portion of Ror2, containing the PRD and S/TRDs (Fig. 4A; Matsuda et al.,2003). Dlxin-1 is known to bind to the homeodomain proteins Msx2 and Dlx5, and regulate their transcriptional functions. In the presence of Ror2, Dlxin-1 is colocalized with Ror2 at the membranous compartments and Msx2 is retained in the nuclei (Fig. 4A). Furthermore, transcriptional activity of Msx2 is regulated by ectopic expression of Ror2, irrespective of its kinase activity. Thus, Ror2 might affect transcriptional functions of Msx2 by regulating intracellular distribution of Dlxin-1 in a tyrosine kinase-independent manner.

Casein kinase Iϵ (CKIϵ), a member of the CKI family of protein Ser/Thr kinases, is also known to associate with Ror2 by means of the C-terminal PRD of Ror2 (Fig. 4B; Kani et al.,2004). Ectopic expression of Ror2 with CKIϵ results in phosphorylation of Ser/Thr residues within the S/TRD2 of Ror2, followed by the autophosphorylation of Ror2 on tyrosine residue(s) within its cytoplasmic PRD. Moreover, Ror2 associates with G protein-coupled receptor kinase 2 (GRK2) and tyrosine phosphorylates it following activation of Ror2 by CKIϵ (Fig. 4B). These results indicate that the tyrosine kinase activity and tyrosine autophosphorylation of Ror2 can be positively regulated by CKIϵ. Of interest, the developmental expression patterns of Dlxin-1 and CKIϵ are similar to that of Ror2 in mouse embryos (Matsuda et al.,2003; Kani et al.,2004), suggesting the role of Dlxin-1 and CKIϵ in Wnt5a/Ror2 signaling during embryogenesis.

Ror2 is phosphorylated on Ser/Thr residues upon Wnt5a stimulation, in a manner dependent on GSK-3, but independent of CKIϵ (Yamamoto et al.,2007). Wnt5a-induced migration of cultured cells can be inhibited by treatment of cells with a GSK3 inhibitor or by siRNA-mediated suppression of GSK-3 expression, suggesting that phosphorylation of Ror2 by GSK3 might be involved in Wnt5a/Ror2 signaling for cell migration.

FUTURE DIRECTIONS

Current Model of Ror-Mediated Noncanonical Wnt Signaling

PCP pathway of noncanonical Wnt signaling, required for the polarized cell migration during developmental morphogenesis, is mediated by the activation of JNK. It has been shown that Ror2 acts as a receptor for Wnt5a, a representative noncanonical Wnt, and mediates the Wnt5a-induced JNK activation and polarized cell migration by means of FLNa-dependent mechanisms (Fig. 2; Oishi et al.,2003; Nishita et al.,2006; Nomachi et al.,2008). Dvl, another important component of PCP pathway, has also been shown to act as an upstream regulator of JNK in noncanonical Wnt signaling. Although it is unclear how Dvl regulates JNK activity in noncanonical Wnt signaling, several studies have shown that CKIϵ phosphorylates Dvl and thereby regulates the downstream signaling of Dvl (Peters et al.,1999; McKay et al.,2001a; Cong et al.,2004; Bryja et al.,2007). We have previously shown that Ror2 is capable of binding to CKIϵ by means of its PRD (Kani et al.,2004). CKIϵ phosphorylates Ror2 on Ser/Thr residues within the S/TRD2 of Ror2 by means of its association with Ror2, resulting in an increase in Ror2 tyrosine kinase activity. Therefore, further study will be required to clarify the possible involvements of CKIϵ and Dvl in Ror2-mediated noncanonical Wnt signaling.

Wnt5a/Ror2 also promotes invasiveness of osteosarcoma cells at least partly by inducing the expression of MMP13 (Enomoto et al.,2009, in press). Degradation of ECM by MMPs is thought to be required for proper cell migration during developmental tissue histogenesis as well as invasion of tumor cells. In fact, it has been shown that MMP14, another member of the MMP-family of proteins, regulates polarized cell migration during zebrafish gastrulation, by interacting genetically with the noncanonical Wnt pathway (Coyle et al.,2008), suggesting that Wnt5a/Ror2/MMP13 signaling might also contribute to regulate polarized cell migration during mammalian embryogenesis.

Does Ror2 also mediate noncanonical Wnt signaling elicited by other Wnts? Wnt11, another noncanonical Wnt molecule, has been shown to regulate several developmental polarized cell movements, including CE movements during gastrulation and migration of neural crest cells (Heisenberg et al.,2000; De Calisto et al.,2005). The ectodomain of Xenopus Ror2 has been shown to bind to Xenopus Wnt11 (Hikasa et al.,2002), suggesting that Ror2 might also be involved in Wnt11-induced noncanonical signaling. In this respect, Cthrc1 may be involved in regulating the specificity of the respective Wnts for Ror2 to activate PCP pathway by stabilizing differentially the interaction of Wnts, including Wnt3a, Wnt5a, and Wnt11, with Ror2 (Yamamoto et al.,2008).

Noncanonical Wnt Signaling in the Nervous System

Accumulating evidence demonstrates that noncanonical Wnt signaling plays essential roles in neuronal development, including neuronal migration, neuronal polarization, axon guidance, dendrite development, and synapse formation (reviewed in Salinas and Zou,2008). Several studies have shown that vertebrate and invertebrate Ror-family RTKs are abundantly expressed in the developing nervous system, indicating that Rors appear to mediate noncanonical Wnt signaling in the establishment of the nervous system (Wilson et al.,1993; Oishi et al.,1997,1999; Forrester et al.,1999; Koga et al.,1999; Takeuchi et al.,2000; Paganoni and Ferreira,2003). As described above, C. elegans CAM-1 plays essential roles in the regulation of neuronal cell migrations, axon guidance, and synaptogenesis (Forrester and Garriga,1997; Forrester et al.,1999; Francis et al.,2005). Although it remains largely unclear whether mammalian Rors also contribute to neuronal development, it has been reported that both Ror1 and Ror2 are highly concentrated at the growing tips of cultured mouse hippocampal neurons, and that knockdown of either Ror1 or Ror2 affects neurite length and frequency of axonal branching in the cultured neurons (Paganoni and Ferreira,2003,2005). Further study will be required to clarify the contributions of Rors in noncanonical Wnt signaling in neuronal development. Ror2 has been shown to act as a receptor or coreceptor for Wnt5a and to mediate Wnt5a-induced migration of cultured cells by activating JNK as described above. Because JNK can mediate several biological processes during neuronal development, including neuronal migration, axon formation, and dendrite morphogenesis, Wnt5a/Ror2 signaling may also be involved in these processes of neuronal development by means of JNK activation (Kawauchi et al.,2003; Eom et al.,2005; Rosso et al.,2005; Oliva et al.,2006; Eminel et al.,2008; Vivancos et al.,2009).

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Citing Literature

Volume239, Issue1

Special Issue on WNT Signaling in Development and Disease

January 2010

Pages 1-15

Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: Their implications in developmental morphogenesis and human diseases

Abstract

STRUCTURE OF THE ROR-FAMILY RECEPTOR TYROSINE KINASES (RTKS)

DEVELOPMENTAL EXPRESSION OF THE ROR-FAMILY RTKS