Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are malignancies characterized by the dependence on B-cell receptor (BCR) signaling and by the high expression of ROR1, the cell surface receptor for Wnt-5a. Both, BCR and ROR1 are therapeutic targets in these diseases and the understanding of their mutual cross talk is thus of direct therapeutic relevance. In this study we analyzed the role of Lyn, a kinase from the Src family participating in BCR signaling, as a mediator of the BCR-ROR1 crosstalk. We confirm the functional interaction between Lyn and ROR1 and demonstrate that Lyn kinase efficiently phosphorylates ROR1 in its kinase domain and aids the recruitment of the E3 ligase c-CBL. We show that ROR1 surface dynamics in migrating primary CLL cells as well as chemotactic properties of CLL cells were inhibited by Lyn inhibitor dasatinib. Our data establish Lyn-mediated phosphorylation of ROR1 as a point of crosstalk between BCR and ROR1 signaling pathways.
Zankruti Dave 1, Olga Vondálová Blanářová 1, Štěpán Čada 1, Pavlína Janovská 1, Nikodém Zezula 1, Martin Běhal 1, Kateřina Hanáková 2, Sri Ranjani Ganji 2, Pavel Krejci 3 4, Kristína Gömöryová 1, Helena Peschelová 2, Michal Šmída 2 5, Zbyněk Zdráhal 2 6, Šárka Pavlová 2 5, Jana Kotašková 2 5, Šárka Pospíšilová 2 5, Vítězslav Bryja 1 7
1 Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
2 Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic.
3Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
4 International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic.
5 Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
6 National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic.
7 Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Brno, Czech Republic.