Tec Kinases Signaling
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Tec Kinases Signaling
Nonreceptor PTKs (Protein Tyrosine Kinases) are essential for the development and activation of B-Cells and T-Cells (Ref.1). The Tec kinases represent the second largest family of mammalian non-RTKs (Receptor Tyrosine Kinases), which are activated in blood cells by stimulation of Cytokine Receptors, Lymphocyte surface antigens, GPCR (G-Protein Coupled Receptors), receptor type PTKs, or Integrins (Ref.2). Tec family members include Tec, BTK (Bruton’s Tyrosine Kinase), ITK (IL-2-Inducible T-cell Kinase)/ EMT/TSK, BMX (Bone Marrow Kinase)/ETK (Epithelial and Endothelial Tyrosine Kinase) and RLK (Resting Lymphocyte Kinase)/TXK. Expression of most Tec kinases is restricted to hematopoietic cells and play important roles in the development or maintenance of the hematopoietic system. Tec, the founding member of the Tec kinase family, is expressed in T-Cells and B-Cells, myeloid cells, and in liver. It is activated in response to BCR (B-Cell Receptor), TCR (T-Cell Receptor)/CD28 or FcEpsilonR (Fc-Epsilon-Receptor) stimulation. CD28 engagement leads to recruitment of Tec (via its SH3 domain) to a proline-rich motif within the cytoplasmic tail of CD28, and overexpression of Tec activates both the IL-2 (Interleukin-2) and IL-4 promoters. Besides BCR and TCR/CD28-mediated signals, Tec is also activated by anti-CD19 and anti-CD38 ligation, and by stimulation of the Cytokine Receptors for IL-3, IL-6, stem cell factor Thrombopoietin, and GMCSF (Granulocyte Macrophage Colony Stimulating Factors) (Ref.1). BTK is found in all cells of hematopoietic lineage except plasma and T-Cells. By contrast, ITK/EMT/TSK and RLK/TXK, is primarily expressed in T-Cells, NK (Natural Killer) cells, mast cells and testes. ITK is activated by various T-Cell surface receptors such as TCR/CD3, CD28, and CD2 (Ref.3).

Although similar in protein organization to the Src family kinases, the Tec kinases possess two distinctive features: (1) TH (Tec Homology) domains, containing proline-rich sequences just upstream of the SH3 domain, which is involved in intra- and intermolecular regulatory interactions; and (2) a PH (Pleckstrin Homology) domain, which binds both to other proteins and to phospholipids and is required for molecular activation. To date, the Tec kinases are the only tyrosine kinases that are known to possess PH domains (Ref.4). TH domains interact with SH3 domains of GRB2 (Growth Factor Receptor-Bound Protein-2), Src family PTKs (Fyn, Lyn, and Hck), Vav or c-Kit (Ref.3). The PH domain is a conserved region that bind both to proteins, including heterotrimeric G-Proteins subunits (G-Alpha, G-Beta and G-Gamma), isoforms of PKC (Protein Kinase-C), Transcription Factors (TFII-I), F-Actin, Vav, Fas, and FAK (Focal Adhesion Kinase), and to phospholipids. Interactions between the PH domain and phopholipids are critical for regulating membrane targeting of most Tec kinases in response to extracellular stimuli. PIP3 (Phosphatidylinositol-3,4,5-Trisphosphate) binding of the PH domain increase BTK kinase activity. Moreover, the combined PH-TH region of BTK also influences protein substrate recognition and binding, and these domains play multiple roles in Tec kinase function (Ref.4). The PH domain with PIP3 targets Tec kinases to specific membrane microdomains, referred to as Rafts or GEMs (Glycolipid Enriched Membranes), where signaling molecules convene upon antigen receptor activation. ITK translocates to GEMs upon TCR/CD3 stimulation in a PIP3 and PH-domain-dependent manner (Ref.4).

The Tec family kinases modulate hematopoietic cellular responses to external stimuli. ITK plays a role in the maturation of thymocytes, is required for intracellular signaling following TCR crosslinking, and is involved in generation of second messengers that mediate cytoskeletal reorganization. Activation of ITK depends on SH2-mediated interactions with phosphorylated signaling partners such as SLP76 and LAT (Linker for Activation of T-Cells) (Ref.6). The Tec family kinases also participate in signal transduction pathways downstream of antigen receptors. In particular, Tec kinases contribute to the PI3K (Phosphatidylinositol-3 Kinase)-dependent phosphorylation and activation of PLC-Gamma isoforms (that cleaves PIP2, Phosphatidylinositol 4,5-Bisphosphate) to generate IP3 (Inositol Triphosphate) and DAG (Diacylglycerol), the concomitant induction of sustained Ca2+ influxes, and the activation of MAPKs (Mitogen Activated Protein Kinases) like JNK (c-Jun Kinase) (Ref.7). In addition to antigen receptor signaling, many other receptor-signaling pathways induce translocation of Tec kinases to the plasma membrane, leading to kinase activation. The chemokine SDF1-Alpha and fMLP (fMet-Leu-Phe), ligands for GPCR, induce translocation of BTK, ITK and Tec to the plasma membrane in a PI3K -dependent manner (Ref.4). In addition to BTK and ITK, other Tec kinases also change localization in response to extracellular stimuli. The PH domain of ETK binds to the FERM domain of FAK upon extracellular matrix stimulation of Integrins , which leads to the activation of ETK. Stimulation of Prolactin receptor, a member of the Cytokine Receptor superfamily, induces activation of Tec and association of both Tec and Vav with the intracellular domain of Prolactin receptor(Ref.4). In other cell types the Tec kinases have been implicated in additional signaling pathways. ETK is a critical intermediate in the STAT (Signal Transducers and Activators of Transcription) phosphorylation and its activation is required for v-Src transformation. ETK/BMX has also been implicated in G-Proteins signaling pathways in endothelial cells, where activation of ETK by G-Alpha subunits lead to activation of transcription factors like NF-KappaB (Nuclear Factor-Kappa-B), c-Jun, c-Fos , Elk1 and SRF (Serum Response Factor). Intriguingly, this pathway involves the small Rho GTPase, an important modulator of the actin cytoskeleton. ETK also activate PAK (p21-Activated Kinase), another molecule implicated in cytoskeletal rearrangements (Ref.4). Several proteins, including Cbl, WASP (Wiskott-Aldrich Syndrome Protein) and SAM68 among others also function in Tec family signaling via their ability to interact with Tec family SH3 domains (Ref.8). Although Tec kinases are associated with TCR signaling pathways, even in lymphocytes, a lack of Tec kinases affects multiple signaling pathways. Tec family has both death-protective and death promoting activities depending on the system. The complexities of their actions through Death Receptors and TLRs (Toll-Like Receptors) may reflect the multiple downstream effectors these kinases can influence. Whether other Tec kinases activate similar signaling intermediates remains unclear.

Tec kinases are activated by multiple membrane receptors and are involved in a variety of downstream responses including Ca2+ influx, proliferation, differentiation, motility apoptosis, gene expression, actin reorganization and adhesion/migration (Ref.9). Mutation of the Tec kinases leads to defective activation of transcription factors. In some cases, these defects are directly attributed to alterations in upstream activators. Mutation of ITK and RLK in T-Cells is associated with decreased activation of the Ca2+ sensitive transcription factor NFAT (Nuclear Factor of Activated T-cells) and the resulting defects in cytokine gene expression (Ref.4). Mutation of the Tec kinases is also associated with alterations in cell survival pathways, including activation of MAP kinases, regulation of Fas-ligand expression as well as interactions of Fas with downstream molecules required for induction of cell death. Nonetheless, Tec family members have both death-protective and death-promoting activities depending on the system. Mutations in BTK are the cause of XLA (X-Linked Agammaglobulinemia) in humans. Tec kinases are required for proper lymphocyte function and development (Ref.5).