The main function of nRTKs is their involvement in signal transduction in activated T- and B-cells in the immune system.
Lyn is activated by stimulation of B-cell receptor, which leads to the recruitment and phosphorylation of Zap70-related nRTK, Syk.
Mutations in the Btk gene are responsible for X-linked agammaglobulinemia,[2][3] a disease characterized by the lack of mature B-cells.
Unlike receptor tyrosine kinases, nRTKs lack receptor-like features such as an extracellular ligand-binding domain and a transmembrane-spanning region.
These enzymes commonly have a modular construction and individual domains are joined together by flexible linker sequences.
Upon the binding of ATP and substrate to nRTKs, catalysis of phosphate transfer occurs in a cleft between these two lobes.
[5] Different preferred sequences around Tyr in Src and Abl suggest that these two types of nRTKs phosphorylates different targets.
The SH3 domain is smaller (~60 residues) and binds proline-containing sequences capable of forming a polyproline type II helix.
These enzymes can bind to activated signaling complexes at the membrane through PH domain interactions with phosphorylated phosphatidylinositol lipids.
[8] Tyrosine kinases of Src family contain the same typical structure: myristoylated terminus, a region of positively charged residues, a short region with low sequence homology, SH3 and SH2 domains, a tyrosine kinase domain, and a short carboxy-terminal tail.
Binding of the two SH2 domains to the tyrosine-phosphorylated ITAM (immunoreceptor tyrosine-based activation motif) sequences in the zeta chain of the T-cell receptor is thought to relieve an inhibitory restraint on the kinase domain, leading to stimulation of catalytic activity.
[18] In contrast, another mutant of the Jak family Jak2, also lacking the pseudo-kinase domain, was able to mediate growth hormone signaling.
These proteins contain a pseudo-substrate sequence thought to interfere with Jak substrate binding and phosphoryl transfer.
This pathologically increased activity of nRTK may be responsible for growth and progression of cancer cells, the induction of drug-resistance, formation of metastasis and tumor neovascularization.
Usually monoclonal antibodies are used for the targeted blockade of RTK, which block the extracellular domain of the receptor and prevent the binding of a ligand.