Integration of T Cell Receptor–dependent Signaling Pathways by Adapter Proteins

Abstract

The initiation of biochemical signal transduction following ligation of surface receptors with intrinsic cytoplasmic tyrosine kinase activity is common for many cell types. T lymphocytes also require activation of tyrosine kinases following T cell receptor (TCR) ligation for maximal stimulation. However, the TCR has no intrinsic tyrosine kinase activity. Instead, the TCR must rely on cytoplasmic tyrosine kinases that localize to the TCR complex and initiate TCR-mediated signaling events. Although much has been learned regarding how these cytosolic tyrosine kinases are activated and recruited to the TCR complex, relatively little is understood about how these initial events are translated into transcriptional activation of genes that regulate cytokine production, cell proliferation, and cell death. Recently, it has become clear that the class of intracellular molecules known collectively as adapter proteins, molecules with modular domains capable of recruiting additional proteins but that exhibit no intrinsic enzymatic activity, serve to couple proximal biochemical events initiated by TCR ligation with more distal signaling pathways.

Quantitative Analysis of Phosphotyrosine Signaling Networks Triggered by CD3 and CD28 Costimulation in Jurkat Cells

“…The most noticeable regulation is that CD3 stimulation increased phosphorylation of Tyr 45 in Grb2-related adaptor protein 2 (Grap2, also known as Grb2-associated protein downstream of Shc (Gads)) by 2.4-fold and Tyr 317 in Src homology 2 domain-containing transforming protein 1 (Shc) by 2.3-fold while CD3/CD28 costimulation further amplified their phosphorylation by 59 and 24%, respectively, suggesting their regulatory roles in response to CD3/CD28 costimulation (Table I). Grap2 shows similar SH3 binding specificity to Grb-2, but is expressed specifically in hemopoietic cells and known to interact with LAT, Sos, dynamin, sam68, and SLP-76, leading to Ag-stimulated endocytosis of TCR, cell proliferation, and cell cycling (3,20). In both self-organizing maps and hierarchical clustering, Grap2 was clustered with CD3 chains, Zap70, and PLC-␥ (Fig.…”

“…Molecular adaptor/scaffold proteins play important roles by linking upstream kinases to downstream kinases or substrates (3,20).…”

CD28 Utilizes Vav-1 to Enhance TCR-Proximal Signaling and NF-AT Activation

“…If this hypothesis was correct, then overexpression of TCR-controlled signaling proteins which are placed upstream of, or interact with, Vav-1 could surrogate overexpression of Vav-1. To this aim, we tested ZAP-70 and the adapter protein SLP-76, two key elements required for NF-AT-induced transcriptional activation (48). Similarly to Vav-1, both proteins are tyrosine phosphorylated following TCR ligation (49,50) and when overexpressed in Jurkat cells they cause an increase of basal (40,42) and Fig.…”

Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK

“…These kinases are critical in the activation of immune cells and have limited expression patterns, with specific family members having lymphoid-specific expression (28). In T cells, members of the first two families of kinases, Lck and Zap-70, are critical for T cell activation as well as development (29). However, Txk/Rlk, a Tec family kinase, seems to be dispensable for T cell activation and development (30).…”