The distributions of the PPI PCCs and the GGI PCCs were plotted in a same figure to show the contrast ( Figure 4A ). In addition, a background distribution of the PCCs of ran-dom probeset pairs was overlaid on the same figure. We let the number of random pairs equal to the number of PPI or GGI pairs, but repeated the process of calculating random PCC distribution 20 times and averaged over the 20 separate random distributions in order to cut down on random fluctuation. Within each run of calculating random PCC distribution, we randomly compiled 2 × n (n = 1037 or 274, for HPRD or IntAct, respectively) pairs of probesets, where each two probeset pairs formed a group. The two PCCs of each group were firstly averaged into a group-level PCC, and the distribution was calculated over the n group-level PCCs. The group-level averaging was devised to mimic the counterpart operation in PPI PCC or GGI PCC calculation. Selective redox regulation of cytokine receptor signaling by extracellular thioredoxin-1 The thiol-disulfide oxidoreductase thioredoxin-1 (Trx1) is known to be secreted by leukocytes and to exhibit cytokine-like properties. Extracellular effects of Trx1 require a functional active site, suggesting a redox-based mechanism of action. However, specific cell surface proteins and pathways coupling extracellular Trx1 redox activity to cellular responses have not been identified so far. Using a mechanism-based kinetic trapping technique to identify disulfide exchange interactions on the intact surface of living lymphocytes, we found that Trx1 catalytically interacts with a single principal target protein. This target protein was identified as the tumor necrosis factor receptor superfamily member 8 (TNFRSF8/CD30). We demonstrate that the redox interaction is highly specific for both Trx1 and CD30 and that the redox state of CD30 determines its ability to engage the cognate ligand and transduce signals. Furthermore, we confirm that Trx1 affects CD30-dependent changes in lymphocyte effector function. Thus, we conclude that receptor–ligand signaling interactions can be selectively regulated by an extracellular redox catalyst. Disulfide bonds have long been recognized as structural elements stabilizing proteins in harsh extracellular environments. More recently, an additional concept has emerged: some disulfide bonds operate as dynamic scaffolds capable of regulated rearrangement into a variety of functional forms (Jordan and Gibbins, 2006) . Consistent with this notion, various cell surface processes have long been known to depend on catalyzed thiol-disulfide exchange including cell adhesion (Essex, 2004) , uptake of bacterial toxins (de Paiva et al, 1993) and viral fusion with the host membrane (Sanders, 2000) . Moreover, a variety of cell surface signaling receptors appear to exist in more than one thiol-disulfide configuration, for example CD28 (Greene et al, 1996) . However, in most cases, neither the catalyst driving thioldisulfide exchange nor the functional differences between the redox forms have been elucidated.