Review Article

Itk: The Rheostat of the T Cell Response

Figure 2

Mode of Itk activation through the T cell receptor. While residing in the cytoplasm, Itk preferentially takes on an inhibited homodimer conformation and in some instances as an inhibited independent cis-conformation. Upon T cell engagement, Itk is able to bind SLP-76 through its SH3 domain and shuttled to the LAT signalosome. Once there, activated ZAP-70 phosphorylates SLP-76 on tyrosine 145 which Itk then binds to with its SH2 domain to solidify the connection at the signalosome. At which time Itk localizes to the plasma membrane by binding PI3K-generated PIP3 with its PH domain and Itk then becomes tyrosine phosphorylated by Lck on tyrosine 511. This leads to Itk’s catalytic activity that first phosphorylates itself on tyrosine 180 culminating in a fully activated enzyme.
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