188 Indeed, investigations in Xenopus oocytes showed that these two residues mediate proton transfer between MCT1/4 and CAII, while CAII–His64 is not involved in proton shuttling between enzyme and transporter but mediates binding of CAII to the MCT1/4 C-terminal tail.184 In analogy to the findings on CAII, it was suggested that CAIX could serve as an extracellular proton antenna for MCTs in cancer cells.114,176,189 The catalytic domain of CAIX seems to lack a homologue cluster to CAII–Glu69 and Asp72. Here, CA2 is linked to cancer.