The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma

Abstract

Tyrosine kinase receptors represent targets of great interest for cancer therapy. Here we demonstrate, for the first time, the importance of the orphan tyrosine kinase receptor, ROR2, in melanoma progression. Using melanoma tissue microarrays we show that ROR2 is expressed predominantly in metastatic melanoma. Because ROR2 has been shown to specifically interact with the non-canonical Wnt ligand, Wnt5A, this corroborates our previous data implicating Wnt5A as a mediator of melanoma metastasis. We show here that increases in Wnt5A cause increases in ROR2 expression, as well as the PKC-dependent, clathrin-mediated internalization of ROR2. WNT5A knockdown by siRNA decreases ROR2 expression, but silencing of ROR2 has no effect on WNT5A levels. ROR2 knockdown does, however, result in a decrease in signaling downstream of Wnt5A. Using in vitro and in vivo metastasis assays we demonstrate that ROR2 is necessary for the Wnt5A-mediated metastasis of melanoma cells. These data imply that ROR2 may represent a novel target for melanoma therapy.

Specifying protein kinase C functions in melanoma

“…Ectopic Wnt5a expression promotes the invasive behavior of melanoma cell lines, and PKC signaling is activated and required for these effects in metastatic melanoma (Bittner et al, 2000;Weeraratna et al, 2002). The effects of Wnt5a in melanoma cells are mediated by binding to the Frizzled-5 and ⁄ or ROR2 receptor and subsequent activation of PKC (O'Connell et al, 2010;Weeraratna et al, 2002). Wnt5a triggers an epithelial-to-mesenchymal transition in a PKC-dependent fashion (Dissanayake et al, 2007).…”

When pathways collide: collaboration and connivance among signalling proteins in development

“…For example, Wnt5a has been variously shown to regulate Ca 2+ , Rac, Src kinases, CaMKII, JNK and β-catenin [44][45][46][49][50][51][52] …”

WNT5A and Its Receptors in the Bone-Cancer Dialogue

“…The expression of WNT5A was found to correlate with the expression of its receptor ROR2, which is also increased in metastatic melanoma tissue. (90) Also, the tumor-promoting (95) Yes (96) Breast cancer (80) ; ovarian cancer (97) …”

“…Yes (19,127,132) Yes (48,133) Breast cancer (81) ; prostate cancer (41) ; melanoma (90,92) ; non-small cell lung cancer (134) ; colorectal cancer (135) ; gastric cancer (136) ; ovarian cancer (131) …”

“…(92) Thus O'Connell and colleagues (90) suggested that WNT5A and ROR2 synergistically increased the metastatic potential in melanoma. Melanoma tumor progression under BRAF inhibitor (BRAFi) treatment has been found to depend on increased WNT5A expression leading to Akt signaling activation through FZD7 and RYK (66) (Fig.…”