Tyrosine kinases as targets for the treatment of rheumatoid arthritis

Abstract

As critical regulators of numerous cell signaling pathways, tyrosine kinases are implicated in the pathogenesis of several diseases, including rheumatoid arthritis (RA). In the absence of disease, synoviocytes produce factors that provide nutrition and lubrication for the surrounding cartilage tissue; few cellular infiltrates are seen in the synovium. In RA, however, macrophages, neutrophils, T cells and B cells infiltrate the synovium and produce cytokines, chemokines and degradative enzymes that promote inflammation and joint destruction. In addition, the synovial lining expands owing to the proliferation of synoviocytes and infiltration of inflammatory cells to form a pannus, which invades the surrounding bone and cartilage. Many of these cell responses are regulated by tyrosine kinases that operate in specific signaling pathways, and inhibition of a number of these kinases might be expected to provide benefit in RA.

Figure 1

Cellular responses mediated by tyrosine kinases that contribute to the pathogenesis of rheumatoid arthritis. Signaling through PDGFRs promotes the proliferation and migration of FLSs, contributing to the formation of a pannus. Migration of endothelial cells to form blood vessels through angiogenesis is promoted by signaling through VEGFRs and regulated by TIE1 and TIE2. Activation of T cells and B cells through T-cell receptors and B-cell receptors, respectively, requires a variety of tyrosine kinases, including Lck, Btk and Syk. Mast cells, which produce numerous inflammatory and degradative factors in the synovium, can be activated by several routes, such as binding of SCF to KIT. M-CSF binding CSF1R promotes the maturation of monocytes into macrophages and subsequent osteoclast formation, which results in bone erosion. Abbreviations: CSF1R, colony-stimulating factor 1 receptor; IL-6, interleukin-6; FLS, fibroblast-like synoviocyte; M-CSF, macrophage colony-stimulating factor; MMP, matrix metalloproteinase; PDGFR, platelet-derived growth factor receptor; RANKL, receptor activator for nuclear factor B ligand; SCF, stem cell factor; TNF, tumor necrosis factor.

Figure 2

Activation of tyrosine kinases. There are two main types of tyrosine kinase: RTKs and non-RTKs. a | Ligand binding increases the stability of transmembrane RTK dimers; motifs within the intracellular domain undergo autophosphorylation, inducing a conformational change that allows ATP and substrate binding. The active kinase catalyzes the transfer of γ-phosphate from ATP to hydroxyl groups of tyrosine residues on the receptor itself or on substrate proteins, creating binding sites or activating substrate proteins, respectively, to promote signal transduction. b | Src-family kinases normally adopt an inactive conformation: the molecule is folded upon itself, such that the activation loop, containing tyrosine 416, is buried between the N-lobe and C-lobe of the kinase domain. This configuration is maintained by interactions between the SH3 domain and the linker region connecting the SH2 with the catalytic domain, and by binding of the SH2 domain to the C-terminal tail following phosphorylation of tyrosine 527. Activation occurs when interactions between the SH2 and SH3 regions and high-affinity binding ligands disrupt these intramolecular interactions, allowing unfolding and revealing tyrosine 416 for autophosphorylation. The mechanism of Src activation is outlined here. Abbreviations: L, ligand; RTK, receptor tyrosine kinase; SH2, SH3 and SH4, Src-homology 2, 3 and 4 domains; UR, unique region.