Lyn, Lupus, and (B) Lymphocytes, a Lesson on the Critical Balance of Kinase Signaling in Immunity

Abstract

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by increased sensitivity to self-antigens, auto-antibody production, and systemic inflammation. B cells have been implicated in disease progression and as such represent an attractive therapeutic target. Lyn is a Src family tyrosine kinase that plays a major role in regulating signaling pathways within B cells as well as other hematopoietic cells. Its role in initiating negative signaling cascades is especially critical as exemplified by Lyn^-/- mice developing an SLE-like disease with plasma cell hyperplasia, underscoring the importance of tightly regulating signaling within B cells. This review highlights recent advances in our understanding of the function of the Src family tyrosine kinase Lyn in B lymphocytes and its contribution to positive and negative signaling pathways that are dysregulated in autoimmunity.

Keywords: B cell; B-cell receptor; Lyn; SFK; autoimmunity; cell signaling; lupus; systemic lupus erythematosus.

Figure 1

Lyn initiates signaling cascades following B cell receptor (BCR) cross-linking. Stimulation of the BCR leads to the activation [green (P)] of Lyn and Syk which results in Igα/β phosphorylation. PLCγ2 activity leads to the hydrolysis of PI(4,5)P2 to IP3 and diacylglycerol (DAG), which stimulates Ca²⁺ mobilization as well as protein kinase C (PKC) and MAPK activation and cell-cycle progression. Phosphorylation of CD19 leads to the membrane recruitment of phosphatidylinositol 3-kinase (PI3K) and activation of Akt, which phosphorylates downstream proteins leading to their inhibition [red (P)] and up-regulation of pro-survival signaling.

Figure 2

Lyn activates negative receptors following B cell receptor (BCR) cross-linking. In addition to initiating positive signaling, Lyn phosphorylates receptors containing immunoreceptor tyrosine inhibitory motifs (ITIMs), leading to the recruitment and activation of phosphatases SHP-1, SHP-2, and SHIP-1. SHP-1 and -2 dephosphorylate (=> arrows) and inhibit the activity of Lyn, Syk PLCγ2 and Btk leading to the down-regulation of positive signaling events. SHIP-1 dephosphorylates PIP3 and prevents activation of Akt signaling pathways.