[1] A signaling cascade is initiated when the receptors bind their respective ligand resulting in cell activation.
Members of the Non-catalytic tyrosine-phosphorylated receptor family share a couple of common features.
Additional characteristics of the receptor family are a rather small (< 20 nm) extracellular domain and the binding to ligands that are anchored to solid surfaces or membranes of other cells.
Members of a class have a high sequence homology and typically share the same gene locus.
Some receptors in this family, however, lack a cytoplasmic tail and therefore associate with adaptor proteins containing the same tyrosine residues.
[3] Adaptor proteins associate to their respective NTR through their transmembrane helixes carrying oppositely charged residues.
[7] Immunoreceptor Tyrosine-based Switch Motifs (ITSMs) with the signature TxYxx(I/V) may induce both activator and inhibitory signals.
[8] Finally, Immunoglobulin Tail Tyrosine Motifs (ITTMs) with a YxNM signature have been found to have a costimulatory effect.
It has been shown that inhibition of tyrosine phosphatases induces phosphorylation in NTRs and signalling even without ligand binding.
[12] It is therefore assumed that a perturbation of SFK and RPTP balance due to ligand binding, leading to stronger kinase activity and hence accumulation of phosphorylated tyrosine residues, is needed for initiation of downstream signalling.
[18][19] Evidence for this model is given by the observation that in T cells, phosphatases CD45 and CD148 segregate from the T-cell receptor upon ligand binding.
[25] Phosphorylated tyrosine residues in cytoplasmic tails of NTRs serve as docking sites for SH2 domains of cytosolic signalling proteins.
Whether a receptor acts as an inhibitor or activator depends on the conserved tyrosine-containing motifs present in its cytoplasmic domain.
[26] Inhibitory motifs (ITIM) on the other hand recruit the cytoplasmic tyrosine phosphates SHP1, SHP2 and the phosphatidylinositol phosphatase SHIP-1.
[27] At any given time, multiple NTR types can be engaged with their receptive ligands, inducing activatory, costimulatory as well as inhibitory signals.