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Annu Rev Immunol. 2018 Apr 26;36:549-578. doi: 10.1146/annurev-immunol-042617-053344.

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

Author information

1
Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA; email: amyand@iastate.edu , jraji@iastate.edu.
2
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA; email: leslie.berg@umassmed.edu , james.conley@umassmed.edu.
3
Department of Biochemistry, University of Utah, Salt Lake City, Utah 84112, USA; email: jiwasa@biochem.utah.edu.

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.

KEYWORDS:

ITK; PLCĪ³1 activation; kinase activation; kinase autoinhibition; tuning T cell responsiveness

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