BCR signaling is required for development of the B cell lineage as well as the response of mature B cells to antigen. The B cell antigen receptor (BCR) is a surface-bound immuoglobulin (Ig) molecule made up of two identical heavy chains and two identical light chains1,2,3,4. The core BCR signaling complex of mature B cells consists of the surface bound Ig molecule (sIg) together with the CD79a and CD79b dimer, also known as Igα and Igβ1,2,3,4. BCR signaling must be flexible and tunable to facilitate a variety of signaling outcomes such as survival, anergy, proliferation, and apoptosis.
Developing B cells express an alternative surface Ig molecule called the pre-BCR that contains a surrogate light chain (VpreB/λ5) in place of a normal κ or λ light chain4. The pre-BCR leads to positive or negative selection depending on the strength of the signal. Other B cells (e.g. marginal zone B cell, germinal center B cells) also exhibit different BCR signal strengths and different accessory molecule requirements. Dysregulation of BCR signaling leads to autoimmunity and cancer.
Upon engagement or cross-linking of the sIg molecules the cytoplasmic tails of CD79a and b are phosphorylated by SRC kinases such as Lyn1,2,3,4. This leads to binding and phosphorylation of Syk. Syk functions as a scaffold for pleckstrin homology (PH) domain-containing kinases Btk and PLCγ2, which are assembled by Blnk (SLP-65)1. Blnk then binds to CD79a and is phosphorylated by Syk. The next major signaling components to be recruited are Btk, Vav-1, PLCγ, and PI3K. Btk links BCR to NFκB activation via PKCβ and activation of the CARMA1—BCL10—MALT1 (CBM) complex1. Vav1 recruits PI3K, which in turn activates AKT, leading to increased cell survival and proliferation1. Cleavage of PIP2 to IP3 and DAG by PLCγ2 leads to release of calcium from the ER and activation of PKC2,3,4. PLCγ2 also activates the Ras/ERK pathway leading to activation of Myc which drives proliferatio2,3,4.
BCR signaling is balanced by groups of positive and negative regulators at the level of Syk, PI3K, and ERK activity1. For example, the phosphatase SHP1 downregulates Syk activity, PTEN downregulates PI3K, and DUSP6 downregulates ERK1.
Fine tuning of BCR signaling is facilitated by varying levels of p-tyr activity associated with different surface Ig isotypes (e.g. IgM vs IgG), resulting in different levels of dependency on accessory molecules4. The CD19/CD81 complex can augment signaling by further recruitment of PI3K, while CD22 and FcγRIIB downregulate BCR signaling by recruiting phosphatases such as SHP1, PTEN, and DUSP6. IL-4, BAFF, TLRs, and CD40L are additional accessory molecules that tune the strength of BCR signaling4. Furthermore, the tyrosine phosphatase CD45 can restore activity of SRC kinases at the cell membrane by dephosphorylating them and re-setting the signaling mechanism1.
The BCR signaling network provides a number of targets for treatment of cancer and autoimmunity4. The oncogenic fusion protein BCR-Abl mimics active BCR/CD79 signaling and is inhibited by the drug imatinib (Gleevec). Other kinase inhibitors have been developed that target elements in the BCR pathway such as PI3Kδ, Syk, and Btk4.
A new approach under investigation takes advantage of so-called autoimmune checkpoints (AIC)1. In this approach, signaling agonists are employed to augment BCR signal strength, mimicking negative selection to trigger deletion of the tumor cells by apoptosis1.
Key Elements in BCR Signaling. The core BCR signaling complex is comprosed of a surface Ig molecule non-covalently associated with CD79a and b, also known as Iga and Igb. CD79a/b recruits the Src family kinase Lyn which activates Syk. Syk serves as a nucleation site for Blnk, Btk, Vav, and PLCg. Together these molecules trigger a complex series of downstream biochemical events leading to coordinated gene expression, cell activation, and proliferation, or death by apoptosis. BCR signaling is downregulated by a group of phosphatases including SHP1, PTEN, and DUSP6 which act to decrease the activity of Syk, PI3K, and ERK respectively.
Below is the entire list of targets involved with BCR Signaling: