The role of competing mechanisms on Lck regulation
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REVIEW
The role of competing mechanisms on Lck regulation Sabin J. Bozso 1,2
&
Jimmy J. H. Kang 3 & Jeevan Nagendran 1,2
Received: 23 March 2020 / Accepted: 10 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Lck is a Src-related protein tyrosine kinase that associates with CD4 and CD8 molecules and is essential to T cell development and T cell activation. Regulatory mechanisms of Lck are diverse and controversy exists regarding the importance of each mechanism. The balance of phosphorylation at the inhibitory and activating Tyr residues is maintained by a balance between CD45 and Csk and is dependent upon intact intracellular trafficking machinery. Current evidence shows that lipid-binding changes depending on Lck conformation and that phosphorylation-induced conformational changes in Lck modulate its kinase activity potentially through regulation of Lck clustering at the plasma membrane. Downstream regulators such as ZAP-70 mediate negative feedback that is dependent on Tyr192 phosphorylation. This review examines the diverse regulation of Lck in detail, highlighting the role of each mechanism on maintaining an appropriate amount of Lck in each conformational state, thus allowing for an efficient, appropriate, and controlled amount of T cell activation following TCR stimulation. Keywords TCR . Lck . Regulation . Immune signaling
Introduction T cell antigen receptor signaling is a complex network of pathways that results in signal transmission from the antigen receptor to the nucleus. The end result of these coordinated signaling pathways differs depending on the context in which they are activated. Antigen receptor signaling is required for positive and negative selection of thymocytes and B cells, the activation of naïve T and B cells, activation of effector function in mature cells resulting in cytokine secretion and cytolytic function, and the activation of memory T and B cells. The activation of naïve T cells requires functional T cell antigen receptor signaling that begins with T cell receptor (TCR) recognition of peptide in the context of major histocompatibility complex (MHC). The TCR forms a complex with CD3, allowing for intracellular signal transduction. All CD3
* Sabin J. Bozso [email protected] 1
Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, Canada
2
Li Ka Shing Health Research Centre, University of Alberta, 4-050, Edmonton, AB, Canada
3
Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
molecules contain an immunoreceptor tyrosine-based activation motif (ITAM) within the cytosol. The ITAM serves as a site of phosphorylation by Src family kinases, such as Lck, that results in the initiation of further downstream signaling events, including recruitment of ZAP-70 which results in the activation of transcription factors promoting T cell proliferation. Phosphorylation of ITAMs by Lck is one of the earliest events after TCR stimulation and essential for TCR signaling. Lck is a Src-related pr
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