Multidomain Control Over TEC Kinase Activation State Tunes the T Cell Response

Abstract

Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation. In resting lymphocytes, TEC kinases are autoinhibited, and multiple interactions between the regulatory and kinase domains maintain low activity. Following TCR stimulation, newly generated signaling modules compete with the autoinhibited core and shift the conformational ensemble to the fully active kinase. This multidomain control over kinase activation state provides a structural mechanism to account for ITK's ability to tune the TCR signal.

Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

“…This suggests that these proteins do not undergo a PH-TH dimerization-dependent activation, which aligns with the idea that other kinases, such as Lck, are largely responsible for activating Itk and Tec once they are recruited to the membrane (26,27). It has been shown that Tec and Itk may function as a tunable signal for gene expression rather than an immediate output upon T cell activation, contrary to the case for Btk and its response to B cell activation (24)(25)(26)42).…”

“…We have shown that the PH-TH modules of the closely related kinases Itk and Tec do not dimerize on the membrane, suggesting that, for Itk and Tec, the enhanced local concentration that results from membrane recruitment might suffice for activation. The molecular differences in kinase domains that are responsible for their differing requirements for PH-TH dimerization requires further study (26). In addition, these differences may provide insights to how T cells and B cells have adapted to different roles in the course of the development of the immune system.…”

“…Btk is also a primary target in the treatment of some types of lymphoma and leukemia, such as with ibrutinib and its derivatives (19,22,23). Furthermore, the study of Btk could elucidate the mechanisms of closely related members of the Tec family, Tec and Itk, which have been shown to control T cell development and proliferation in a similar manner (24)(25)(26).…”

CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine

“…IL-2-inducible T cell kinase (ITK) is a Tec-family tyrosine kinase predominantly expressed in T cells and important in modulating TCR signal strength (1)(2)(3). ITK regulates the differentiation of naive CD4 + T cells into various Th cell subsets (4)(5)(6)(7)(8) and is required for effector T cell responses that protect against certain infections, as well as those that contribute to allergic and autoimmune responses (4,7,(9)(10)(11).…”

Noncatalytic Bruton's tyrosine kinase activates PLCγ2 variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells

“…BTK is one of the five members of strongly conserved Tec family of non-receptor tyrosine kinases, also including the IL-2inducible T cell kinase ITK, TEC proper, RLK, and BMX (11). While all five Tec variants are expressed in cells of the hematopoietic lineage, BTK and ITK are key regulators of B cell and T cell transmembrane signaling, respectively (12). Mutations of the human and mouse BTK and Btk genes functionally affecting BTK were found to be associated with human X-linked agammaglobulinemia (XLA) and murine Xlinked immunodeficiency (xid) (11).…”