The Wnt5a/Ror2 noncanonical signaling pathway inhibits canonical Wnt signaling in K562 cells.
Wnt5a has been shown to be involved in cancer progression in a variety of tumor types, and regulates multiple intracellular signaling cascades; it is a representative ligand that activates a noncanonical Wnt signaling pathway. The mechanism governing how Wnt5a determines the specificity of these pathways and the relationship with tumorigenesis is still unknown. In this study, we aimed to clarify the tumor suppressor role of Wnt5a in leukemogenesis. In particular, we focused on Ror2 functioning as a Wnt5a receptor to mediate noncanonical Wnt signaling, which inhibits canonical Wnt signaling in K562 cells. We found that up-regulation of Wnt5a expression increased Ror2 expression in K562 cells and Wnt5a and Ror2 were co-expressed in the cytoplasm. Also, Wnt5a induced the intrnalization of Ror2. Co-immunoprecipitation experiments were performed to determine whether Ror2 binds to Wnt5a, and inhibits Wnt5a binding with Frizzled4 and LRP5 in Wnt5a treated K562 cells. Wnt5a had no effect on total ß-catenin expression levels, but regulated tyrosine phosphorylation of ß-catenin and translocation of ß-catenin from the cytoplasm to the nucleus. Furthermore, expression of Wnt5a was associated with suppression of ß-catenin/TCF-dependent transcriptional activity and down-regulated the expression of cyclin D1, a downstream target gene of the canonical Wnt signaling pathway. We hypothesize that Wnt5a plays the role of a tumor suppressor in leukemogenesis through the Wnt5a/Ror2 noncanonical signaling pathway that inhibits Wnt canonical signaling.
Department of Clinical Hematology, Third Military Medical University, Chongqing 400038, PR China.
Yuan
Y
Yuan
Chang Chun
CC
Niu
Gang
G
Deng
Zhao Quan
ZQ
Li
Jing
J
Pan
Chen
C
Zhao
Zong Lin
ZL
Yang
Wei Ke
WK
Si
D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020014:K562 Cells / Q000378:metabolism* / Q000648:ultrastructure; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D019938:Cyclin D1; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors