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Annual Review of Immunology

Volume 36, 2018

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.

Keyword(s): ITK, kinase activation, kinase autoinhibition, PLCγ1 activation, tuning T cell responsiveness
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2018-04-26
2025-04-26
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Multidomain Control Over TEC Kinase Activation State Tunes the T Cell Response
Annual Review of Immunology 36, 549 (2018); https://doi.org/10.1146/annurev-immunol-042617-053344
/content/journals/10.1146/annurev-immunol-042617-053344
/content/journals/10.1146/annurev-immunol-042617-053344
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Supplementary Data

  • Supplemental Animation 1: The narrated molecular animation shows how ITK converts from its closed, autoinhibited conformation to a more open active state. Active ITK is associated with the SLP-76/LAT complex at the membrane. Like ITK, PLCγ1 adopts a closed, autoinhibited conformation prior to its association with active ITK at the SLP-76/LAT/membrane complex. Once docked onto ITK, PLCγ1 is activated by ITK mediated phosphorylation which then triggers release of PLCγ1 from the ITK complex. Activated PLCγ1 then acts on its membrane associated substrate, PIP2. PLCγ1 mediated hydrolysis of PIP2 yields IP3 and DAG which serve as important second messengers that trigger further signaling. The extent of ITK activation, which in this review we suggest is tied to TCR signal strength, will likely determine the extent of second messenger produced.

  • Article Type: Review Article

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