FIGURE 3. Regulation of Lck and negative feedback pathways.
(A) Lck is a Src family kinase (SFK) and is localized to the inner leaflet of the plasma membrane through lipidation of its N-terminus where it associates with the cytoplasmic domain of the CD4/CD8 coreceptors. Lck possess a catalytic kinase domain, two regulatory domains, and several sites of phosphorylation. The activity of the catalytic kinase domain is controlled by regulating its conformation. Conformational control is achieved through phosphorylation of Lck regulatory sites. The C-terminal tail of Lck, when phosphorylated, is bound by the SH2 regulatory domain through an intramolecular interaction to stabilize the inactive autoinhibited conformation. In contrast, the active conformation of Lck is stabilized by trans-autophosphorylation of the activation loop within the kinase domain. (B) Recent studies have indicated that a pool of Lck is basally active in resting T cells. Increasing the abundance of active Lck molecules can alter affinity discrimination and potentiate T cell activation in response to low affinity ligands. (C) Inhibitory feedback pathways are proposed to regulate the abundance of active Lck molecules in a T cell. Phosphorylation of Y192 within the SH2 domain of Lck is proposed to disrupt the activation of Lck by CD45 and therefore reduce the abundance of active Lck and TCR sensitivity. (D) Because the inhibitory kinase Csk is cytoplasmic, recruitment of Csk to the plasma membrane through the Lckdependent phosphorylation of inhibitory adaptor proteins (e.g., PAG) can decrease active Lck abundance.