Fig. 10. G12 as a check-point in TJ regulation. At baseline (A), claudins from neighboring cells interact with each other in the paracellular space and with ZO-1 in the TJ. The TJ protein complex contains numerous proteins. In this figure, ZO-1, ZO-2 and ZO-3 are designated ZO. Src might interact directly or indirectly with the ZO complex. G12 directly interacts with ZO-1 and ZO-2, and Hsp90 is probably not constitutively localized in this domain but is recruited to the activated G12 complex (denoted with ^* in B). Activated G12 (QL mutation or thrombin) activates Src (denoted with ^* in B) leading to increased tyrosine phosphorylation of ZO-1 and ZO-2 (P-Y). (C) Phosphorylation of ZO-1 and ZO-2 leads to disruption of the ZO-1 protein complex, intracellular localization of claudin 1 and loss of barrier function. In addition to the loss of barrier function, under some conditions of persistent activation, this could lead to persistent disassembly of the TJ. Once TJs are disrupted and stimulated to reassemble (as in the calcium switch), activation of G12 (using Hsp90 and Src) leads to a brake on TJ assembly.