Tec Kinase Signaling

Non-receptor protein tyrosine kinases (PTKs) are essential for the development and activation of B-cells and T-cells. Tec kinases represent the second largest family of mammalian non-RTKs, which are activated in blood cells by stimulation of cytokine receptors, lymphocyte surface antigens, GPCRs and integrins. Tec family members include Tec, BTK, ITK/ EMT/TSK, BMX/ETK and RLK /TXK. Expression of most Tec kinases is restricted to hematopoietic cells and play an important role in the development or maintenance of the hematopoietic system. Tec, the founding member of the Tec kinase family is expressed in T-cells, B-cells and myeloid cells. It is activated in response to BCR, TCR/CD28 or FcεR stimulation. CD28 engagement leads to recruitment of Tec via its SH3 domain to a proline-rich motif within the cytoplasmic tail of CD28. Tec is also activated by receptors for IL-3, IL-6, SCF, thrombopoietin and GMCSF. BTK is found in cells of hematopoietic lineage with the exception of plasma and T-cells. By contrast, ITK/EMT/TSK and RLK/TXK are primarily expressed in T-cells, NK-cells and mast cells. ITK is activated by various T-cell surface receptors such as TCR/CD3, CD28 and CD2.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 cross-linking, and is involved in generation of second messengers that mediate cytoskeletal reorganization. The Tec family kinases also participate in signal transduction pathways downstream of antigen receptors. In particular, Tec kinases contribute to the PI3K dependent phosphorylation and activation of PLC-γ. In addition to antigen receptor signaling, many other receptor signaling pathways induce translocation of Tec kinases to the plasma membrane, leading to kinase activation. Ligands for GPCR induce translocation of BTK, ITK and Tec to the plasma membrane in a PI3K-dependent manner. 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. ETK is a critical intermediate in the STAT phosphorylation and its activation is required for v-Src transformation. ETK/BMX has also been implicated in G-protein signaling pathways in endothelial cells. ETK also activates p21-Activated Kinase (PAK), another molecule implicated in cytoskeletal rearrangements. Tec family has both death protective and death promoting activities depending on the system. The complexities of their actions through death receptors and TLRs may reflect the multiple downstream effectors these kinases can influence. Tec kinases are involved in a variety of physiological process such as proliferation, differentiation, motility apoptosis, gene expression, actin reorganization and cell adhesion/migration.