Figure 6.

CaM binds the Itk PH domain in a positive feedback loop that potentiates Itk activity, intracellular Ca²⁺ release, and IL-17A production. Binding of Itk to PIP₃ promotes Itk activation and the subsequent phosphorylation and activation of PLC γ1. PLCγ1 cleaves PIP₂ to produce DAG and IP₃, which binds IP₃ receptors on the ER. The IP₃ receptor is a ligand-gated Ca²⁺ channel, and its activation increases Ca²⁺ levels in the cytosol. Increased cytosolic Ca²⁺ activates CaM, which has at least two effects on T cell activation: (1) Ca²⁺/CaM binds to Itk’s PH domain, enhancing its interaction with PIP₃ and Itk activity. (2) Ca²⁺/CaM binds to and activates calcineurin, a phophatase that dephosphorylates NFAT, allowing NFAT translocation to the nucleus where it drives the transcription of IL-17A. Thus, CaM binding to Itk’s PH domain completes a positive feedback loop that potentiates the downstream effects of Itk. PM, plasma membrane; ER, endoplasmic reticulum; Itk, IL-2-inducible tyrosine/T cell kinase; PLCγ1, phospholipase C gamma 1; CaM, calmodulin; NFAT, nuclear factor of activated T cells; IP₃R, IP₃ receptor.