Receptor tyrosine kinases

Unlike receptor tyrosine kinases, nRTKs lack receptor-like features such as an extracellular ligand-binding domain and a transmembrane-spanning region. The most of nRTKs are localized in the cytoplasm, but some nRTKs are anchored to the cell membrane though amino-terminal modification.

Another Src family member Lyn is involved in signaling mediated by B-cell receptor. Lyn is activated by stimulation of B-cell receptor, which leads to the recruitment and phosphorylation of Zap70-related nRTK, Syk.

CD4 and CD8 receptors on T lymphocytes require for their signaling the Src family member Lck. When antigen binds to T-cell receptor, Lck becomes autophosphorylation and phosphorylates the zeta chain of the T-cell receptor, subsequently another nRTK, Zap70, binds to this T-cell receptor and then participates in downstream signaling events that mediate transcriptional activation of cytokine genes.

Unlike the receptor tyrosine kinases, nRTKs are cytoplasmic enzymes. There was found 32 non-receptor tyrosine kinases in a human. nRTKs regulate for example cell growth, proliferation, differentiation, adhesion, migration and apoptosis and they are critical components in the regulation of the immune system.

The main function of nRTKs is their involvement in signal transduction in activated T- and B-cells in the immune system; signaling by many receptors is dependent on nRTKs including T-cell receptors, B-cell receptors, IL-2 receptors, Ig receptors, erythropoietin receptors and prolactin receptors.

Tyrosine kinase catalytic domain of nRTK includes ~275 residues. The catalytic domain can be divided to small and large regions, ATP binds to a small region and protein substrate binds to a large region. Upon binding of ATP and substrate to nRTKs, catalysis of phosphate transfer occurs in a cleft between these two regions.

It was found that nRTKs have some sequence preference around the target Tyr. Src preferred sequence is Glu–Glu/Asp–Ile–Tyr–Gly/Glu–Glu–Phe and Abl preferred sequence is Ile/Val–Tyr–Gly–Val–Leu/Val. Different preferred sequences around Tyr in Src and Abl suggest that these two types of nRTKs phosphorylates different targets.

Non-receptor tyrosine kinases contain also domains that mediate protein-protein, protein-lipid, and protein-DNA interactions. One of the protein-protein interaction domains in nRTKs are the Src homology 2 (SH2) and 3 (SH3) domains. The longer SH2 domain (~100 residues) binds phosphotyrosine (P-Tyr) residues in a sequence-specific manner. The SH3 domain is smaller (~60 residues) and binds proline-containing sequences capable of forming a polyproline type II helix.

Some nRTKs without SH2 and SH3 domains possess some subfamily-specific domains used for protein-protein interactions. For example specific domains that target enzymes to the cytoplasmic part of cytokine receptors (Jak family) or two domains: an integrin-binding domain and a focal adhesion-binding domain (Fak family).

Domain structure of Janus kinases, JH = JAK homology domain

The JAK-STAT system consists of three main components: (1) a receptor (green), which penetrates the cell membrane (2) Janus kinase (JAK) (yellow), which is bound to the receptor and (3) Signal Transducer and Activator of Transcription (STAT) (blue), which carries the signal into the nucleus and DNA. The red dots are phosphates. After the cytokine binds to the receptor, JAK adds a phosphate to the receptor. This attracts the STAT proteins, which are also phosphorylated and bind to each other, forming a dimer. The dimer moves into the nucleus, binds to the DNA, and causes transcription of genes. Enzymes that add phosphate groups are called protein kinases.

In addition to SH2 and SH3 domains, Btk/Tec subfamily of nRTKs possess pleckstrin homology (PH) domain. These PH domains bind to phosphorylated phosphatidylinositol lipids. These enzymes can bind to activated signaling complexes at the membrane through PH domain interactions with phosphorylated phosphatidylinositol lipids.

Дата добавления: 2014-01-14