Phosphorylated immunoreceptor signalling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases []. Motif may be dually phosphorylated on tyrosine that links antigen receptors to downstream signalling machinery.
Lyn is a member of the Src non-receptor type tyrosine kinase family. It plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance [, ]. It also mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils [, , ]. Lyn plays an essential role in the transmission of signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins [, ].This entry represents the SH2 domain of Lyn.The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR []. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5 []. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules []. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
The adaptor protein 3BP2/SH3BP2 is a cytoplasmic adaptor that contributes to the regulation of immune responses []. The protein-tyrosine kinase Syk phosphorylates 3BP2 which results in the activation of Rac1 through the interaction with the SH2 domain of Vav1 and induces the binding to the SH2 domain of the upstream protein-tyrosine kinase Lyn and enhances its kinase activity []. 3BP2 has a positive regulatory role in IgE-mediated mast cell activation []. In lymphocytes, engagement of T cell or B cell receptors triggers tyrosine phosphorylation of 3BP2 []. 3BP2 is required for the proliferation of B cells and B cell receptor signaling. Mutations in the 3BP2 gene are responsible for cherubism resulting in excessive bone resorption in the jaw [].This entry represents the SH2 domain of SH3BP2.
The adaptor protein 3BP2/SH3BP2 is a cytoplasmic adaptor that contributes to the regulation of immune responses []. The protein-tyrosine kinase Syk phosphorylates 3BP2 which results in the activation of Rac1 through the interaction with the SH2 domain of Vav1 and induces the binding to the SH2 domain of the upstream protein-tyrosine kinase Lyn and enhances its kinase activity []. 3BP2 has a positive regulatory role in IgE-mediated mast cell activation []. In lymphocytes, engagement of T cell or B cell receptors triggers tyrosine phosphorylation of 3BP2 []. 3BP2 is required for the proliferation of B cells and B cell receptor signaling. Mutations in the 3BP2 gene are responsible for cherubism resulting in excessive bone resorption in the jaw [].
Signal transduction by T and B cell antigen receptors and certain receptorsfor Ig Fc regions involves a conserved sequence motif, termed animmunoreceptor tyrosine-based activation motif (ITAM). It is also found in thecytoplasmic domain of the apoptosis receptor. Phosphorylation of the two ITAMtyrosines is a critical event in signal transduction. All (p)2ITAMs, but nottheir nonphosphorylated counterparts, induced extensive protein tyrosinephosphorylation in permeabilised cells. After binding of the ligand via an SH2domain, phosphorylation of the two conserved tyrosines of ITAM creates binding sites for downstream signalling molecules and thus enables the initiation of signalling events. This phosphorylation was found to reflect activation of the src family kinases Lyn and Syk. Different ITAMs may preferentially activate distinct signalling pathways as a consequence of distinct SH2 effector binding preference [, ]. Furthermore, in viruses, ITAMs may play key roles in viral pathogenesis by regulating viral clearance, immune cell activation, immune cell recruitment through binding of cellular kinases and thereby down regulate their function [].This motif can be found in one to three copies and in association with the Ig-like domain. Proteins currently known to contain an ITAM motif are:Mammalian alpha and beta immunoglobulin proteins, TCR gamma receptors, FCR gamma receptors subunits, CD3 chains receptors and NFAT activation molecule.Hantavirus cytoplasmic elements.
This family consists of several Gammaherpesvirus latent membrane protein (LMP2) proteins. Epstein-Barr virus (strain GD1) (HHV-4) (Human herpesvirus 4) is a human gammaherpesvirus that infects and establishes latency in B lymphocytes in vivo. The latent membrane protein 2 (LMP2) gene is expressed in latently infected B cells and encodes two protein isoforms, LMP2A and LMP2B, that are identical except for an additional N-terminal 119 aa cytoplasmic domain which is present in the LMP2A isoform. LMP2A is thought to play a key role in either the establishment or the maintenance of latency and/or the reactivation of productive infection from the latent state. It modulates B-cell receptor signal transduction through its association with the cellular tyrosine kinases Lyn and Syk via specific motifs at the N-terminal tail domain. LMP2A also modulates the immune system reducing infected B cells recognition by EBV-specific CD8+ T cells []. The significance of LMP2B and its role in pathogenesis remain unclear. It is suggested that it may be a negative regulator of LMP2A [, ].
