Disease relevance of Tec

• Although that hypothesis was further strengthened by the knowledge that mutations in Btk cause agammaglobulinemia in humans, we have only limited information concerning the molecular interaction through which Tec kinases exert their effects [1].
• In screening of interleukin 3 (IL-3)-dependent myeloid leukemia cells for protein tyrosine kinases, we observed that all cell lines examined expressed high levels of Tec transcripts [2].

High impact information on Tec

• Although initial studies demonstrated a role for these proteins in TCR-mediated activation of phospholipase C-gamma, recent data indicate that Tec family kinases also regulate actin cytoskeletal reorganization and cellular adhesion following TCR stimulation [3].
• The Tec family tyrosine kinases are now recognized as important mediators of antigen receptor signaling in lymphocytes [3].
• Tec family kinases in T lymphocyte development and function [3].
• Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk [4].
• The Tec family tyrosine kinase, Itk, is critical for PLC-gamma1 activation downstream of the TCR [5].

Biological context of Tec

• Physical mapping of the Tec and Gabrb1 loci reveals that the Wsh mutation on mouse chromosome 5 is associated with an inversion [6].
• Thus, we looked for other Tec family kinases that could be expressed in lymphoid cells and involved in T cell signal transduction [7].
• Txk also restored PLCgamma2/calcium signaling but, unlike other Tec kinases, functioned in a phosphatidylinositol 3-kinase-independent manner and failed to reconstitute apoptosis [8].
• Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation [9].
• Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion [10].

Anatomical context of Tec

• Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk [11].
• Here we show that Tec-deficient mice developed normally and had no major phenotypic alterations of the immune system [11].
• Although Tec/Btk(null) mice were able to form germinal centers, the response to T cell-dependent antigens was impaired [11].
• However, Tec is up-regulated upon T-cell activation and in Th1 and Th2 cells [12].
• Here we demonstrate that Lyn can phosphorylate tyrosine residues of the Tec protein, and thereby activate Tec in 3T3 fibroblasts [13].

Associations of Tec with chemical compounds

• This interaction involves the Tec SH3 domain and the proline-rich motifs in CD28 [7].
• Surprisingly, the presence of the pleckstrin homology (PH) domain of Tec is not required for this accumulation, and despite a strong activation of 3'-phosphorylated phosphoinositide lipids synthesis during the synapse formation, the Tec PH domain is not redistributed to the T cell plasma membrane [14].
• In contrast to the complete inhibition of Tec kinase-dependent calcium signaling, activation of the serine/threonine kinase Akt was partially preserved during BCR and FcgammaRIIb1 coligation [15].

Physical interactions of Tec

• We could previously show that, through the Tec-homology domain, Tec is bound to Lyn kinase both in vitro and in vivo [13].

Enzymatic interactions of Tec

• Both Lyn and Tec were capable of phosphorylating Dok-1 [16].
• We could reveal that the C-terminal half of the Tec N-terminal unique domain (NTec2 region) can bind to a set of tyrosine-phosphorylated cellular proteins in vitro in an IL-3-dependent manner [17].
• Interestingly, Tec is shown to be tyrosine phosphorylated and activated by the G-CSF stimulation in both cell growth and differentiation mechanisms [18].

Regulatory relationships of Tec

• In this study, we show that Tec protein is expressed at substantially lower levels in primary T and B cells relative to Itk and Btk, respectively [12].
• Because Tec is coexpressed with Lyn in many hematopoietic cell types, it has been intriguing to investigate the biological role of the Tec-Lyn association [13].
• Moreover, expression of Galpha12 and Galpha13 stimulates autophosphorylation and transphosphorylation activities of Tec [19].
• IL-3 stimulation was also shown to induce kinase activity of Tec [20].
• Taken together, our study shows that Tec and Btk regulate M-CSFR signaling-induced macrophage survival and provides a novel link between Tec family kinases and the regulation of caspase-11 and GM-CSFRalpha expression [21].

Other interactions of Tec

• This altered physical map can be explained by an inversion on the Wsh chromosome located proximally to the Kit locus and spanning the 2.8 Mb Pdgfra-Tec chromosomal segment [6].
• We also show that Tec can phosphorylate p62(dok), one CD28-specific substrate, whereas Itk cannot [7].
• However, coexpression of Tec has little effect on the phospho-tyrosine-contents of Lyn [13].
• Here, we demonstrate that Tec, expressed in T cells, is activated following TCR/CD3 or CD28 ligation and interacts with CD28 receptor in an activation-dependent manner [7].
• In this study we show that Tec kinases are required for TCR-mediated up-regulation of adhesion via the LFA-1 integrin [10].

Analytical, diagnostic and therapeutic context of Tec

• Dynamic regulation of Tec kinase localization in membrane-proximal vesicles of a T cell clone revealed by total internal reflection fluorescence and confocal microscopy [22].
• Using site-directed mutagenesis we show that both sites can bind the Tec SH3 domain; site 1 (155KTLPPAP161) binds intramolecularly, while site 2 (165KRRPPPPIPP174) cannot and binds in an intermolecular fashion [23].
• By PCR analysis, approximately equal levels of Tec transcripts containing the intact SH3 domain and containing the 22 amino acid deletion were found in hematopoietic cells [2].
• Supportive western blotting of testis, adult liver, spleen and heart of adult C.B-17 mice with the use of anti-Tec antibody demonstrated a heavy 70 kDa band in the liver and testis, and a much weaker, small band in the heart and spleen [24].

References