Melania Tesio: Laboratory of Onco-Hematology, Institut Necker Enfants Malades (INEM), Institut National de la Recherche Médicale (INSERM) U1151, Paris, France
SYK is a tyrosine kinase that plays crucial roles in B-cells. Activated following engagement of the B-cell receptor (BCR), SYK initiates the proximal BCR signaling by triggering two distinct downstream pathways, namely the Ca2+/NFAT signaling via BLNK and BTK, and the PI3K-AKT signaling via CD19. In autoreactive B-cells or premalignant B-cells presenting an oncogenic activation of the BCR signaling, SYK-mediated BCR hyperactivation triggers negative selection and cell death.
Structurally similar to SYK is ZAP70, a tyrosine kinase initiating the TCR signaling in T-cells. Despite SYK and ZAP70 play analogous roles in B and T-cells, their expression is strictly segregated respectively in the B and T lineages. Reporting in Molecular Cell, Teresa Sadras and colleagues demonstrate that this developmental segregation is required to prevent B-cell malignancies.
The authors demonstrated that ZAP70 is aberrantly expressed in multiple B-cell malignancies, where it competes with SYK for binding common BCR signalosome substrates, such as BLNK and BTK. In this way, ZAP70 reduces the activation of the Ca2+-NFAT pathway thus altering the signaling threshold required to trigger the negative selection. In parallel, ZAP70 promotes SYK-mediated activation of the CD19-PI3K pathway, which mediates a tonic survival signal (Figure). Hence, by diverging SYK signaling from Ca2+-NFAT to PI3K activation, ZAP70 re-wires the BCR signaling to subvert the negative selection and promote cell survival.
Sadras T, et al. Mol Cell. 2021;81(10):2094-2111.e9.