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Integrated signaling and transcriptome analysis reveals Src-family kinase individualities and novel pathways controlled by their constitutive activity

The enzymatic activity of Src-family kinase (SFKs) members Lck and Lyn is crucial to lymphocyte development and function. Lck has a T-cell restricted pattern of expression, however its ectopic presence has been documented in numerous pathological conditions. Amongst those, the erroneous presence of Lck in Chronic Lymphocytic Leukemia (CLL) B-cells has been suggested as a relevant factor for disease pathophysiology. However, the exact impact of Lck on the B-cell signaling apparatus remains unclear. In this work we sought to investigate the mechanistic basis of ectopic Lck in B-cell activation events. We examined the onset of proximal B-cell Receptor (BCR) signaling pathways and transcriptome alterations under the influence of ectopic Lck and compared it to events elicited by the predominant B-cell SFK member, Lyn. Our studies pinpointed signalling pathways exclusively governed by the constitutive activity of the two SFKs, excluding interferences from receptor/co-receptor engagement, influence of the microenvironment, alterations on their stereochemical integrity, or modulation of their regulators such as Csk or CD45, which also affect additional substrates. Lck- and Lyn-transduced signals sufficed to drive signalling events reminiscent of B-cells found in an activated state. We further discovered that the two kinases display differential susceptibility to mechanisms designed to prevent the onset of unscheduled signalling events, by keeping global levels of SFK activity under control. Finally, our analyses revealed a yet unrecognized role of SFK-driven signals in tipping the balance of cellular stress response regulation.