Towards unraveling the complexity of T cell signal transduction

Abstract

Activation of resting T lymphocytes through the T cell antigen receptor complex is initiated by critical phosphorylation and dephosphorylation events that regulate the function and interaction of a number of signaling molecules. Key elements in these reactions are members of the Src, Syk and Csk families of protein tyrosine kinases (PTKs) and the phosphotyrosine phosphatases (PTPases) that regulate and/or counteract them, such as CD45. The PTKs can autophosphorylate and phosphorylate each other at multiple sites and, as the result of these interactions, they are induced to phosphorylate other cellular proteins. These phosphorylation events lead to modulation of enzymatic activities and/or serve as binding sites for other signaling molecules having phosphotyrosine-binding Src homology 2 (SH2) domains. As a result, these proteins translocate to the receptor complexes and are juxtaposed to the kinases that phosphorylate them. Some of the SH2-domain-containing polypeptides lack enzymatic activities and, instead, serve as adapter molecules that couple the signal to downstream effectors, such as regulators of the Ras proteins, and further into serine/threonine-specific protein kinase cascades. Through largely unknown steps these reactions lead to the transcription of previously silent genes, activation of lymphocyte effector functions, progression through the cell cycle and cell proliferation.

CD148, a membrane protein tyrosine phosphatase, is able to induce tyrosine phosphorylation on human lymphocytes

“…As can be observed in Fig. 1, after CD3 crosslinking a neat pattern of protein tyrosine phosphorylation was detected, as has been previously described [7]. In a similar way, after CD148 crosslinking also a clear pattern of phosphorylation could be observed.…”

A Discrete Three-amino Acid Segment (LVI) at the C-terminal End of Kinase-impaired ErbB3 Is Required for Transactivation of ErbB2

“…One scenario is that a third protein with tyrosine kinase activity is bound to the cytoplasmic domain of ErbB3 and that this kinase phosphorylates ErbB2. This would be similar to the transactivation mechanism observed in cytokine receptor and T-cell antigen receptor signaling (31,32). If the activity of a third kinase was directly regulated by ErbB3, the kinase activity of ErbB2 would not be required for receptor phosphorylation.…”

Molecular Cloning of a T Cell-specific Adapter Protein (TSAd) Containing an Src Homology (SH) 2 Domain and Putative SH3 and Phosphotyrosine Binding Sites

“…Search for pro-tein motifs was also performed using the compilation of protein sequence analysis programs at the UK HGMP Resource Center, Cambridge, UK. 2 The alignment of multiple SH2 domains was performed using the pfscan program. 3 …”

“…Many signaling proteins, with or without catalytic function, contain SH3 domains (2), which are conserved regions of 60 -85 aa residues involved in cell polarization and in subcellular localization of proteins (38). The consensus SH3 binding motif is PXXP, with different SH3 domains having different preferences for particular sequence motifs (3,32).…”