Transmembrane adaptor proteins positively regulating the activation of lymphocytes

Abstract

Engagement of the immunoreceptors initiates signaling cascades resulting in lymphocyte activation and differentiation to effector cells, which are essential for the elimination of pathogens from the body. For the transduction of these immunoreceptor-mediated signals, several linker proteins termed transmembrane adaptor proteins (TRAPs) were shown to be required. TRAPs serve as platforms for the assembly and membrane targeting of the specific signaling proteins. Among seven TRAPs identified so far, LAT and LIME were shown to act as a positive regulator in TCR-mediated signaling pathways. In this review, we will discuss the functions of LAT and LIME in modulating T cell development, activation and differentiation.

Keywords: LAT (Linker for activation of T cells); LIME (Lck-interacting transmembrane adaptor protein); TRAP (transmembrane adaptor protein); lymphocyte.

Figure 1

Signaling pathways mediated by LAT. Upon TCR engagement, Src-family kinase, Lck, is activated and phosphorylates the tyrosine residues within ITAM motifs on CD3γ/ε/ζ chains. Subsequently, Syk-family kinase, ZAP-70, is recruited through its SH2 domain and become activated by phosphorylation by Lck. Activated ZAP-70 phosphorylates the tyrosine residues within TBSMs of raft-associated LAT, allowing the recruitment of other signaling molecules possessing SH2 domains or phosphotyrosine-binding (PTB) domains including Gads, Grb2, PLCγ1 at the membrane proximal sites. Through the constitutive interaction with Gads, SLP-76 are recruited to LAT and become phosphorylated by ZAP-70. The recruitment of Itk via SLP-76 is required for full activation of PLCγ1. Activated PLCγ1 hydrolyze the phosphatidylinositol 4, 5 bisphosphate(PIP₂) to inositol 3, 4, 5-triohosphate (IP₃) and diacylglycerol (DAG), leading to the calcium mobilization and NF-κB activation. Tyrosine-phosphorylated SLP-76 also provides docking sites for Vav, Nck and ADAP, forming signaling complexes for actin reorganization. Together with Grb2/Sos-mediated Ras/MAPK activation, these signaling pathways cooperatively activate the IL-2 poduction and T cell proliferation. These positive signaling pathways can be negatively regulated by the inhibition of Lck activity by PAG-associated Csk kinase.