Non-receptor tyrosine kinases, also known as cytoplasmic tyrosine kinases, are a subfamily of tyrosine kinases, which are responsible for transferring a phosphate group to a tyrosine residue in proteins. Unlike the other group of tyrosine kinases, the receptor tyrosine kinases, the non-receptor tyrosine kinases lack transmembrane domain and are located inside of the cells. Based on sequence similarities of kinase domains, non-receptor tyrosine kinases are further classified into 10 subfamilies, including ABL, ACK, CSK, FAK, FES, FRK, JAK, SRC, TEC and SYK. In addition to the kinase domain, non-receptor tyrosine kinases also have several signaling or protein-protein interaction domains, such as SH2 and PH domains.
The enzymatic activities of both receptor tyrosine kinases and non-receptor tyrosine kinases are tightly controlled by cells. For example, nonproliferating cells have less phosphorylated tyrosine residues in proteins. Compared to the receptor tyrosine kinase, the activation mechanisms of non-receptor tyrosine kinases are more complicated, which involve heterogeneous protein-protein interaction to enable transphosphorylation. Due to the presence of cellular inhibition proteins and lipids and through intramolecular autoinhibition, non-receptor tyrosine kinases are maintained in an inactivated state. Through intracellular activation signals, non-receptor tyrosine kinases are recruited to transmembrane receptors and phosphorylated by other kinases.
Non-receptor tyrosine kinases regulate multiple cellular processes, such as proliferation, differentiation and adhesion, and are also critical to regulating immune systems. Furthermore, studies suggest that non-receptor tyrosine kinases are targets for cancer therapies. For example, Src, a non-receptor tyrosine kinase, is the first proto-oncogene, which is resulted in two Nobel Prize to date.