Roles of Btk Syk and PI3K in Bcell biology

Btk, Syk, and PI3K are expressed in B-cells as well as other cell types which may play a role in disease, including monocytes, macrophages, and mast cells. Given the validation of biologic therapies targeting B-cells, this chapter will focus on advances in targeting these kinases to modulate B-cell activity. Btk, Syk, and PI3K are cytoplasmic kinases that sit at the apex of the B-cell signaling cascade and are in position to profoundly impact downstream signaling events and consequent B-cell activation (Figure 1).

Btk is expressed in B-cells, monocyctes, mast cells, and osteoclasts, but not T-cells. Btk is essential for B-cell development and defects in the Btk gene lead to X-linked agammaglobulinemia (XLA) in humans, which is characterized by a lack of circulating B-cells and serum immunoglobulins [22,23]. Btk-deficient mice are resistant to the development of SLE and collagen-induced arthritis (CIA) [24]. Antigen binding to the BCR activates Src family and PI3 kinases, and Btk is recruited to the plasma

Btk Pi3k Syk Fcr Signaling
Figure 1 Btk, Syk, and PI3K in B-cell signaling. (See Color Plate 11.1 in the Color Plate Section)

membrane via its PH domain where it is transphosphorylated at Y551 in the activation loop, followed by autophosphorylation at Y223 [25,26]. Fully activated Btk phosphorylates phospholipase-Cg2 (PLCy2), leading to increased calcium flux, nuclear factor-kappa B (NFkB) activation, and ultimately B-cell activation and proliferation.

Syk is primarily expressed in hematopoeitic cells, as well as synoviocytes and vascular endothelial cells. Upon ligation of cell-surface immu-noreceptors (e.g., BCR, FcR), Src family kinases phosphorylate the cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs). Syk binds to phosphorylated ITAMs via its SH2 domain and is subsequently activated. Syk then activates downstream pathways, including PI3K, MAPK, and PLCg, leading to B-cell activation and cytokine release. Syk is a key element of the BCR signaling cascade, and Syk-deficient mice suffer from an early block in B-cell development [27,28]. Syk is also critical for FceR-mediated degranulation of mast cells [29,30].

The class 1 PI3 kinases (a, p, g, 8) all effect the same conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol tripho-sphate (PIP3). The g and 8 isoforms are of most interest for inflammatory indications due to their selective expression in leukocytes. PI3K8 appears to have a more prominent role in B-cells, while PI3Kg has a stronger association with T-cell function [31,32]. B-cells isolated from PI3K8 kinase-inactive knock-in mice do not proliferate in response to BCR stimulation, indicating an essential role for PI3K8 in B-cell function [33]. PI3K8 is located downstream of the BCR and CD19 (Figure 1) and plays a key role in establishing a signalosome that also involves Btk and Syk. The biology of PI3K 8 and g has been reviewed recently [34-38].

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