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

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 obl...

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Bibliographic Details
Published in:Annual review of immunology 2018-04, Vol.36 (1), p.549-578
Main Authors: Andreotti, Amy H, Joseph, Raji E, Conley, James M, Iwasa, Janet, Berg, Leslie J
Format: Article
Language:English
Subjects:
ITK
kinase activation
kinase autoinhibition
PLCĪ³1 activation
tuning T cell responsiveness
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Summary: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.
ISSN:0732-0582
1545-3278
DOI:10.1146/annurev-immunol-042617-053344