title: Wnt5a induces ROR1/ROR2 heterooligomerization to  enhance leukemia chemotaxis and proliferation.
abstract: Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. We found that Wnt5a enhanced proliferation and migration of chronic lymphocytic leukemia (CLL) cells and that these effects were blocked by the humanized anti-ROR1 mAb cirmtuzumab (UC-961). Treatment of CLL cells with Wnt5a induced ROR1 to oligomerize with ROR2 and recruit guanine exchange factors (GEFs), which activated Rac1 and RhoA; siRNA-mediated silencing of either ROR1 or ROR2 or treatment with UC-961 inhibited these effects. Using the ROR1-deficient CLL cell line MEC1, we demonstrated that ectopic ROR1 expression induced ROR1/ROR2 heterooligomers, which recruited GEFs, and enhanced proliferation, cytokine-directed migration, and engraftment potential of MEC1 cells in immune-deficient mice. Notably, treatment with UC-961 inhibited engraftment of ROR1+ leukemia cells in immune-competent ROR1-transgenic mice. Molecular analysis revealed that the extracellular Kringle domain is required for ROR1/ROR2 heterooligomerization and the cysteine-rich domain or intracellular proline-rich domain is required for Wnt5a-induced recruitment of GEFs to ROR1/ROR2. This study identifies an interaction between ROR1 and ROR2 that is required for Wnt5a signaling that promotes leukemia chemotaxis and proliferation.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Liguang
authors.initials: L
authors.lastname: Chen
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.forename: George F
authors.initials: GF
authors.lastname: Widhopf
authors.forename: Zhouxin
authors.initials: Z
authors.lastname: Shen
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wu
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.forename: Steven P
authors.initials: SP
authors.lastname: Briggs
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002633:Chemotaxis; D064593:Heterografts; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; C107953:RAC1 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C078716:ROR1 protein, human; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D020830:rac1 GTP-Binding Protein