Engineering receptor kinases mainly involve a domain swapping or shuffling strategy in which a receptor protein or another HK contributes their functional module. The domain swapping in HKs implies that these proteins are flexible, allowing the construction of new kinases using a rational design strategy. The domain swapping strategy has been used to produce chimeric TCRSs that include chemotaxis proteins. There are several periplasmic chemotactic receptors, such as Tsr, Tar, Trg, and Aer, that recognize specific chemicals, and they can be coupled with the cytoplasmic domain of EnvZ to allow signal transduction . EnvZ is the most studied HK protein that regulates the phosphorylation state of OmpR in response to osmolarity changes. OmpR is an RR protein responsible for the controlled expression of ompF and ompC genes encoding for the membrane porin proteins OmpF and OmpC, respectively. Aside from OmpR, EnvZ can also regulate the phosphotransfer of 11 different RRs found in E. coli . Because the EnvZ–ompR complex in E. coli is a well-studied TCRS that is widely-distributed in bacteria, the DHp and CA domains of EnvZ are commonly used for the domain swapping strategy. A good example of this is the hybridization of Tar, a chemoreceptor transmembrane protein that can detect aspartate and EnvZ. By replacing the cytoplasmic signaling domain of Tar protein with the cytoplasmic kinase/phosphatase domain of EnvZ, the hybridized proteins were able to carry out both the sensing capability of Tar for aspartate and the regulation capability of EnvZ towards OmpR thereby consequently activating ompC . This strategy also worked in the hybridization of Trg protein and EnvZ, allowing the recognition of ribose-binding peptides and activation expression of ompC . In addition to functioning as chemotactic receptors, HK domains are also involved in light sensing, and kinases that sense C4-dicarboxylate, sugar, aspartate, and acidic amino acids have been engineered with the EnvZ cytoplasmic domain to provide a better sensing ability for the desired substance (Table 1). This approach to engineering novel two-component sensor proteins not only acts as a high throughput screening system but also provides knowledge of the newly identified two-component signaling pathways.