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Jennifer R. Brown, MD, PhD


Is Lyn Kinase the Bridge Between BCR and ROR1 Signaling Pathways in CLL?

By: Gavin Calabretta, BS
Posted: Tuesday, April 26, 2022

During embryonic development, receptor tyrosine kinase–like orphan receptor proteins (RORs) are heavily expressed and later become restricted postnatally. However, ROR1 and ROR2 upregulation has been observed in many adult cancers. More specifically, most chronic lymphocytic leukemia (CLL) cells are highly ROR1-positive. According to a study published in Frontiers in Cell and Developmental Biology, Lyn, an Src family kinase, is associated with the interaction between the ROR1 and BCR pathways and may prove to be a potential therapeutic target in CLL.

Vítězslav Bryja, PhD, of Masaryk University, Brno, Czech Republic, and colleagues stated that this was the first study to show the interaction between the two pathways. “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,” the authors commented.

Patient samples were obtained from the University Hospital Brno. Testing for interactions between Lyn and ROR1, the investigators observed HEK-293T cells in which both proteins were overexpressed. It was discovered that the deletion of the intracellular domain of ROR1 stopped the binding to Lyn, indicating the ROR1 kinase domain may be a crucial interaction interface for Lyn. In addition to the strong ROR1 phosphorylation detected, it was also observed that dasatinib, a pan-Src kinase family inhibitor, did not interfere with the interaction between ROR1 and Lyn, but it did result in substantial decreases in ROR1 phosphorylation and surface dynamics; according to the authors, this finding shows that ROR1 trafficking and activity may be contingent on Lyn kinase activity. When they later tested for the recruitment of downstream proteins because of ROR1 phosphorylation, it was noted that c-CBL—a member of a family of RING finger E3 ligases—properly interacted with ROR1 only when wild-type Lyn was present. Thus, the investigators believe that c-CBL recruitment was dependent on Lyn-mediated phosphorylation of ROR1.

Disclosure: The study authors reported no conflicts of interest.

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