Tyrosine kinases in inflammatory dermatologic disease

Abstract

Tyrosine kinases (TKs) are enzymes that catalyze the phosphorylation of tyrosine residues on protein substrates. They are key components of signaling pathways that drive an array of cellular responses including proliferation, differentiation, migration, and survival. Specific TKs have recently been identified as critical to the pathogenesis of several autoimmune and inflammatory diseases. Small-molecule inhibitors of TKs are emerging as a novel class of therapy that may provide benefit in certain patient subsets. In this review, we highlight TK signaling implicated in inflammatory dermatologic diseases, evaluate strategies aimed at inhibiting these aberrant signaling pathways, and discuss prospects for future drug development.

Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Figures

Figure 1

Receptor tyrosine kinase activation. A. In the absence of ligand binding, receptor tyrosine kinases (TKs) usually exist in the cell membrane in a monomeric and non-phosphorylated form. B. Ligand binding to the extracellular domain causes conformational changes that induce and stabilize oligomerization of the receptor TKs, leading to autophosphorylation of their cytoplasmic domains. The active kinase catalyzes the transfer of phosphate groups (P) to substrate molecules, thereby promoting signal transduction, including through MAPKs, Akt, and STATs, and downstream effector functions. The conformational changes involved in receptor TK activation may also promote signal transduction by releasing inhibitory constraints on substrate molecules. C. In the presence of a TK inhibitor (TKI), the cytosolic components of the receptor TK fail to effectively oligomerize and autophosphorylate, which prevents signal transduction and effector function.

Figure 2

Activation of tyrosine kinases. A. Tyrosine kinases (TKs) contain a substrate-binding domain, an ATP-binding site, and a catalytic site where the phosphate group (P) will be transferred. The substrate is the molecule to which the phosphate will be transferred. Under basal conditions, TKs exist in an inactive (“closed”) conformation (not shown), and phosphorylation of TKs stabilizes the active (“open”) kinase conformation that permits catalytic transfer of phosphate groups to substrate molecules. B. An activated TK transfers a phosphate group from ATP (or GTP) to a tyrosine residue on a substrate molecule. C. Phosphorylation of substrates by TKs is an important cellular mechanism by which a signal is propagated from one part of the cell to another and leads to various effector functions. D. TK inhibitors usually binds the kinase at the ATP-binding site, thus preventing ATP from binding and transferring a phosphate group to the substrate, and consequently preventing the active substrate from signaling to other parts of the cell. Selectivity of TK inhibitors is made possible by generating inhibitors that bind to specific chemical pockets adjacent to the ATP-binding site.

Figure 3

Cell types and responses mediated by exemplary kinases that may contribute to the pathogenesis of inflammatory dermatologic disorders. Fibroblast proliferation, differentiation, migration, and survival are promoted by signaling through PDGFRs, as well as through TGFβ receptors via c-Abl. Signaling through VEGF or EGF receptors induces proliferation, migration, survival, and adhesion of keratinocytes and endothelial cells. Syk contributes to B-cell receptor signaling, inducing B-cell proliferation and activation. JAK3 propagates T-cell signals through Type I cytokine receptors that contain the common gamma chain, thereby promoting T-cell proliferation, activation, and development. Tyk2 is important in Type I IFN signaling, which leads to cellular responses including IFN signature gene upregulation, DC differentiation, and Th responses. Abbreviations: DC, dendritic cell; EGFR, epidermal growth factor receptor; IFN-R, interferon receptor; PDGFR, platelet-derived growth factor receptor; TGF, transforming growth factor; VEGFR, vascular endothelial cell growth factor receptor; Syk, spleen tyrosine kinase; JAK3, janus kinase 3.