Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach.

Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach.
Biol Chem. 2018 Nov 01;:
Authors: Kulathu Y, Zuern C, Yang J, Reth M
Abstract
Upon activation of the B cell antigen receptor (BCR), the spleen tyrosine kinase (Syk) and the Src family kinase Lyn phosphorylate tyrosines of the immunoreceptor tyrosine-based activation motif (ITAM) of Igα and Igβ which further serve as binding sites for the SH2 domains of these kinases. Using a synthetic biology approach, we dissect the roles of different ITAM residues of Igα in Syk activation. We find that a leucine to glycine mutation at the Y+3 position after the first ITAM tyrosine prevents Syk binding and activation. However, a preactivated Syk can still phosphorylate this tyrosine in trans. Our data show that the formation of a Syk/ITAM initiation complex and trans-ITAM phosphorylation is crucial for BCR signal amplification. In contrast, the interaction of Lyn with the first ITAM tyrosine is not altered by the leucine to glycine mutation. In addition, our study suggests that an ITAM-bound Syk phosphorylates the non-ITAM tyrosine Y204 of Igα only in cis. Collectively, our reconstitution experiments suggest a model whereby first trans-phosphorylation amplifies the BCR signal and subsequently cis-phosphorylation couples the receptor to downstream signaling elements.
PMID: 30465710 [PubMed - as supplied by...

Source: Biological Chemistry - November 23, 2018 Category: Chemistry Tags: Biol Chem Source Type: research