A Story of Kinases and Adaptors: The Role of Lck, ZAP-70 and LAT in Switch Panel Governing T-Cell Development and Activation

Abstract

Specific antigen recognition is one of the immune system’s features that allows it to mount intense yet controlled responses to an infinity of potential threats. T cells play a relevant role in the host defense and the clearance of pathogens by means of the specific recognition of peptide antigens presented by antigen-presenting cells (APCs), and, to do so, they are equipped with a clonally distributed antigen receptor called the T-cell receptor (TCR). Upon the specific engagement of the TCR, multiple intracellular signals are triggered, which lead to the activation, proliferation and differentiation of T lymphocytes into effector cells. In addition, this signaling cascade also operates during T-cell development, allowing for the generation of cells that can be helpful in the defense against threats, as well as preventing the generation of autoreactive cells. Early TCR signals include phosphorylation events in which the tyrosine kinases Lck and ZAP70 are involved. The sequential activation of these kinases leads to the phosphorylation of the transmembrane adaptor LAT, which constitutes a signaling hub for the generation of a signalosome, finally resulting in T-cell activation. These early signals play a relevant role in triggering the development, activation, proliferation and apoptosis of T cells, and the negative regulation of these signals is key to avoid aberrant processes that could generate inappropriate cellular responses and disease. In this review, we will examine and discuss the roles of the tyrosine kinases Lck and ZAP70 and the membrane adaptor LAT in these cellular processes.

Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking

“…Full ZAP70 activation thereafter phosphorylates the critical adaptors LAT at tyrosine residues including Y191 to coordinate the downstream signaling cascade. 1,37,47 Our protein analysis revealed that the activating phosphorylations of LCK, ZAP70, and LAT in T-ALL cells were consistently abolished after treatment with a low concentration of 1232030-35-1, indicating an overall inhibited state of pre-TCR-LCK signaling. This resulted in not only robust in vitro antiproliferation effects in T-ALL cells, but also promising therapeutic effects in T-ALL mice.…”

“…Previous reports indicated that the phosphorylation of LCK at Y394 is essential for its activation. 47 Upon TCR stimulation, LCK phosphorylates the immunoreceptor tyrosine-based activation motif (ITAM) within the TCR, which leads to sequential ZAP70 phosphorylation at Y319 and Y493. Full ZAP70 activation thereafter phosphorylates the critical adaptors LAT at tyrosine residues including Y191 to coordinate the downstream signaling cascade.…”

“…This interaction leads to intercepted subsequent activating phosphorylation cascades of LCK, which is responsible for a series of aggressive phenotypes of leukemia cells. Previous reports indicated that the phosphorylation of LCK at Y394 is essential for its activation . Upon TCR stimulation, LCK phosphorylates the immunoreceptor tyrosine-based activation motif (ITAM) within the TCR, which leads to sequential ZAP70 phosphorylation at Y319 and Y493.…”

Immune Rejection Mediated by prf1 and gzmb Affects the Colonization of Fat Greenling (Hexagrammos otakii) Spermatogonia in Heterotransplantation

“…This regulation of lck activity is crucial for recognizing foreign antigens without attacking non-foreign tissues, thereby maintaining immune tolerance. Zeta-chainassociated protein kinase 70 (zap-70), a critical tyrosine kinase in the T cell receptor (TCR) signaling pathway, operates alongside lck in the early events of TCR signaling, ultimately activating T cells [39]. Furthermore, zap-70 is involved in regulating the immune response of T cells by controlling the intensity and timing of signaling, ensuring appropriate immune responses and avoiding immunopathological processes due to overactivation [40].…”