Syk and pTyr'd: Signaling through the B cell antigen receptor

Abstract

The B cell receptor (BCR) transduces antigen binding into alterations in the activity of intracellular signaling pathways through its ability to recruit and activate the cytoplasmic protein-tyrosine kinase Syk. The recruitment of Syk to the receptor, its activation and its subsequent interactions with downstream effectors are all regulated by its phosphorylation on tyrosine. This review discusses our current understanding of how this phosphorylation regulates the activity of Syk and its participation in signaling through the BCR.

Sensitive kinase assay linked with phosphoproteomics for identifying direct kinase substrates

“…S1). Human DG75 B cells were first treated with pervanadate, an inducer of oxidative stress to activate Syk (18), and potent inhibitor of protein-tyrosine phosphatases, to elevate the overall level of phosphotyrosine-containing proteins in the cell and to increase the yield of phosphopeptides. Proteins were extracted from cell lysates, digested with trypsin, and peptides containing phosphotyrosine were isolated using a cocktail of immobilized antibodies against phosphotyrosine (4G10, PT66, and PY20).…”

“…To demonstrate the KALIP strategy, we used spleen tyrosine kinase (Syk) as our target kinase. Syk is a 72-kDa protein-tyrosine kinase known to have a crucial role in adaptive immune receptor signaling, in particular in B cells by coupling the B-cell receptor (BCR) for antigen to multiple intracellular signaling pathways and also in modulating cellular responses to inducers of oxidative stress in a receptor-independent fashion (17,18). However, Syk also mediates diverse biological functions including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation, and vascular development (17).…”

Syk Interacts with and Phosphorylates Nucleolin To Stabilize Bcl-xL mRNA and Promote Cell Survival

“…The Syk protein tyrosine kinase is best known for its roles in hematopoietic cells, where it is required for signaling through immune recognition receptors that contain immunoreceptor tyrosine-based activation motifs (ITAMs) (1,2). Examples include the antigen receptor on B cells (BCR), the high-affinity IgE receptor of mast cells, and IgG receptors on neutrophils and macrophages.…”

“…I n addition to its well-studied role in normal immune cell biology (1,2), the Syk protein tyrosine kinase plays an increasingly recognized, albeit poorly understood, role in tumorigenesis. Constitutively active Syk has been reported to promote the survival of non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and Epstein-Barr virus-associated B-cell lymphoma (3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Inhibitors of B-Cell Receptor Signaling for the Treatment of Chronic Lymphocytic Leukemia

“…Several studies highlight the critical role of Syk in the molecular mechanisms regulating BCR signaling [25]. Syk as a key component of BCR signaling pathway is critical for normal and malignant B-cell development and proliferation [26,27]. Inhibition of Syk pathway prevents CLL cells from interacting with the microenvironment and inhibition of Syk promotes proapoptotic signals [28,29].…”