Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach.
BCR
ITAM
Lyn
Syk
signal amplification
synthetic biology
Journal
Biological chemistry
ISSN: 1437-4315
Titre abrégé: Biol Chem
Pays: Germany
ID NLM: 9700112
Informations de publication
Date de publication:
26 03 2019
26 03 2019
Historique:
received:
29
06
2018
accepted:
08
11
2018
pubmed:
23
11
2018
medline:
18
12
2019
entrez:
23
11
2018
Statut:
ppublish
Résumé
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 found that a leucine to glycine mutation at the Y+3 position after the first ITAM tyrosine prevents Syk binding and activation. However, a pre-activated 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.
Identifiants
pubmed: 30465710
doi: 10.1515/hsz-2018-0308
pii: hsz-2018-0308
doi:
Substances chimiques
Receptors, Antigen, B-Cell
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
555-563Subventions
Organisme : Medical Research Council
ID : MC_UU_00018/3
Pays : United Kingdom
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