Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Abstract

The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk. Whereas Tec deficiency did not affect phosphorylation of phospholipase Cγ or Ca2+ influx, it was associated with significantly increased activation of the intracellular Akt/S6 kinase signaling pathway upon BCR and CD40 stimulation. The increased S6 kinase phosphorylation in Tec-deficient B cells was dependent on Btk kinase activity, as ibrutinib treatment restored pS6 to wild-type levels, although Btk protein and phosphorylation levels were comparable to controls. In Tec-deficient mice in vivo, B cell responses to model Ags and humoral immunity upon influenza infection were enhanced. Moreover, aged mice lacking Tec kinase developed a mild autoimmune phenotype. Taken together, these data indicate that in mature B cells, Tec and Btk may compete for activation of the Akt signaling pathway, whereby the activating capacity of Btk is limited by the presence of Tec kinase.

Role of Bruton’s tyrosine kinase in B cells and malignancies

“…Importantly, phosphorylation of AKT is positively regulated by BTK [ 56 ]. The BTK family member TEC, which can partly compensate for BTK [ 57 ], may on the other hand limit the capacity of BTK to activate AKT [ 58 ].…”

Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors

“…As such, we are currently evaluating the utility of these new molecules in B-cell related lymphocytic diseases where TECkinases play a prominent role. 17,51…”

Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies

“…Similarly, a recent study from our group showed that two pathways downstream of the BCR are involved in inactivation of the kinase GSK3 in chronic lymphocytic leukemia (CLL) cells, resulting in a different capacity of SYK, BTK, and PI3Kδ inhibitors to reduce the expression of the antiapoptotic protein Mcl-1, which is negatively regulated by GSK3 [ 20 ]. Finally, although BTK is located downstream of PI3K, several studies have suggested that there is also crosstalk in the opposite direction and that BTK can enhance the activity of the PI3K/AKT pathway in BCR-stimulated cells [ 21 , 22 , 23 , 24 , 25 , 26 ]. The mechanism behind this effect is still not completely understood, but involvement of BTK in the phosphorylation of the adaptor BCAP and in the production of the PI3K substrate PIP2 have been proposed as potential explanations [ 22 , 24 ].…”