Review article

Positive and negative regulation of T-cell activation through kinases and phosphatases



The sequence of events in T-cell antigen receptor (TCR) signalling leading to T-cell activation involves regulation of a number of protein tyrosine kinases (PTKs) and the phosphorylation status of many of their substrates. Proximal signalling pathways involve PTKs of the Src, Syk, Csk and Tec families, adapter proteins and effector enzymes in a highly organized tyrosine-phosphorylation cascade. In intact cells, tyrosine phosphorylation is rapidly reversible and generally of a very low stoichiometry even under induced conditions due to the fact that the enzymes removing phosphate from tyrosine-phosphorylated substrates, the protein tyrosine phosphatases (PTPases), have a capacity that is several orders of magnitude higher than that of the PTKs. It follows that a relatively minor change in the PTK/PTPase balance can have a major impact on net tyrosine phosphorylation and thereby on activation and proliferation of T-cells. This review focuses on the involvement of PTKs and PTPases in positive and negative regulation of T-cell activation, the emerging theme of reciprocal regulation of each type of enzyme by the other, as well as regulation of phosphotyrosine turnover by Ser/Thr phosphorylation and regulation of localization of signal components.

  • Csk
  • kinase
  • Lck
  • phosphatase
  • T-cell
  • Zap


  • Abbreviations used: Cbp, Csk-binding protein; ERK, extracellular signal-regulated protein kinase; HePTP, haematopoietic PTPase; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; JNK, c-Jun N-terminal kinase; KIM, kinase-interaction motif; LMPTP, low-Mr PTPase; MAP kinase, mitogen-activated protein kinase; MEK, MAP kinase/ERK kinase; MKP, MAP kinase phosphatase; PAG, phosphoprotein associated with glycosphingolipid-enriched membrane domains; PEP, PEST-enriched protein tyrosine phosphatase; PKA, protein kinase A; PTK, protein tyrosine kinase; PTPase, protein tyrosine phosphatase; PTP-MEG2, PTPase from megacaryocytes 2; PTP-PEST, PTPase with PEST sequences; SH2, Src homology 2; SH3, Src homology 3; SHP1, SH2-domain-containing protein tyrosine phosphatase 1; SLP-76, SH2-domain-containing leucocyte protein of 76kDa; SMAC, supramolecular activation cluster; TCPTP, T-cell PTPase; TCR, T-cell receptor; VHR, VH1-related; VHX, VHR-related MKPX.