The dual role of the novel Wnt receptor tyrosine kinase, ROR2, in human carcinogenesis

Abstract

The Wnt signaling pathway is involved in the development and progression of many human cancers, yet attempts to target the pathway therapeutically have been disappointing to date. The recent discovery that the ROR2 receptor tyrosine kinase (RTK) is a novel Wnt receptor provides the potential to target the non-canonical Wnt pathway for cancer treatments. As a member of the RTK superfamily of surface receptors ROR2 appears to possess dual roles as a tumor suppressor or activator depending on tumor type. This review will explore the dual role of ROR2 in tumorigenesis and provide an up to date analysis of current literature in this rapidly expanding field. Wnt Signaling PathwayWnt signaling is essential for embryonic development and cellular processes including differentiation, polarity, migration, invasion, adhesion and survival.1 These same cellular processes are crucial components of tumorigenesis and metastasis, and hence therapeutic strategies to target Wnt signaling in human cancer are increasingly being investigated. Deregulation of the Wnt signaling pathway has been implicated in numerous cancers including colorectal, breast, ovarian, and prostate cancer (reviewed in Ref. Non-canonical Wnt signaling has been less clearly characterized than canonical signaling. It encompasses at least two different signaling pathways-the Wnt/Ca 2þ pathway involving CaMKII, Protein-kinase-C (PKC) and NFAT, and the planar-cell polarity (PCP) pathway thought to signal through RhoA, Rac and c-Jun N-terminal kinase (Jnk). Importantly, the non-canonical Wnt signaling pathway has been shown to antagonise canonical Wnt signaling (Fig. 1). This observation has raised the possibility that activating the non-canonical Wnt pathway in cancers driven by hyperactivated canonical Wnt signaling may be a novel therapeutic approach. [3][4][5] Traditionally, the two arms of the pathway were defined by the specific Wnt ligand involved in activating the pathway. For example, Wnt1 and Wnt3a were thought to activate the canonical pathway, and Wnt5a and Wnt11 were thought to activate the non-canonical pathway. However, therapy targeted at the ligand level is unlikely to be successful, as studies have shown that in specific contexts, a number of the noncanonical Wnt ligands, particularly the prototypical non-canonical effector ligand Wnt5a, are also capable of initiating canonical Wnt signaling.6,7 Furthermore, the key canonical Wnt ligand, Wnt3a was recently shown to be capable of activating PKC, a non-canonical target. 8 These findings provide new insights into the pathway and throw into question the traditional ligand-mediated model of Wnt signaling. 9,10 A new paradigm is emerging within the Wnt field whereby the specific signaling pathway is not determined by the intrinsic properties of a particular Wnt ligand, but rather by the receptor configuration on the surface of a given cell. 10The ROR Family of Receptor Tyrosine KinasesThe two members that belong to the ROR family of receptor tyrosine kinases (RTKs) were originally referred to as orphan

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

“…Acquisition of ROR1 by such cells may be an important step in leukemogenesis, allowing the neoplastic complex with LRP5/6 in response to canonical Wnt factors, such as Wnt3a. Through such a mechanism, Wnt5a inhibits the capacity of Wnt factors, such as Wnt3a, to induce canonical Wnt signaling (27,33,(49)(50)(51). Furthermore, studies have demonstrated that isolated overexpression of ROR2 in 293 cells actually enhanced the capacity of Wnt5a to repress expression of β-catenin target genes (28).…”

“…On the other hand, ROR2 also can repress transcription of Wnt target genes and modulate Wnt signaling by sequestering canonical Wnt ligands, thereby serving as a tumor suppressor in different cell contexts (27,28). Although studies have shown that ROR1 or ROR2 can associate with other proteins to modify canonical Wnt signaling or induce noncanonical signaling (29,30), ROR1 and ROR2 are each considered to function independently of one another.…”

Human Cytomegalovirus Modulates Expression of Noncanonical Wnt Receptor ROR2 To Alter Trophoblast Migration

“…In contrast, Wnt5a ligand mediates intracellular signaling via a ␤-catenin-independent (noncanonical) Wnt pathway to regulate cell polarity and migration in a variety of tumor types, including metastatic melanoma (40), thyroid carcinoma (41), and colon cancer (42). Wnt5a associates with tyrosine kinase-like orphan receptor 2 (ROR2) (43,44), which leads to Rho GTPase (RhoA and Rac)-dependent activation of the Wnt-Jun N-terminal kinase (JNK) pathway and activation of the WntCa2 ϩ pathway through calcium/calmodulin-dependent protein kinase II (CaMKII) (45)(46)(47). The role of this noncanonical Wnt pathway in trophoblast migration has not been investigated so far and needs to be elucidated given the importance of Wnt signaling in embryonic development and disease.…”

Knockdown of receptor tyrosine kinase-like orphan receptor 2 inhibits cell proliferation and colony formation in osteosarcoma cells by inducing arrest in cell cycle progression

“…instance, the protein expression of ROR2 was reported to be significantly decreased in hepatocellular carcinoma (HCC) tissues compared with adjacent non-tumorous tissues, and loss of ROR2 expression was associated with poor prognosis, suggesting that ROR2 may act as a tumor suppressor in HCC (26). By contrast, ROR2 was suggested to play an oncogenic role in certain other cancers, including melanoma, renal cell cancer and oral squamous cell carcinoma (27)(28)(29).…”