The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells.
Animals
B-Lymphocytes
/ immunology
Biomarkers
Computational Biology
/ methods
Enzyme Activation
Gene Knockout Techniques
Germinal Center
/ immunology
Humans
Mice, Knockout
PTEN Phosphohydrolase
/ metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt
/ metabolism
Receptors, Antigen, B-Cell
/ metabolism
Signal Transduction
Substrate Specificity
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
16
09
2018
accepted:
12
03
2019
pubmed:
24
4
2019
medline:
10
7
2019
entrez:
24
4
2019
Statut:
ppublish
Résumé
B cell antigen receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to optimize selection for high-affinity B cells. In GCBC, BCR signals are constrained, but the mechanisms are not well understood. Here we describe a GC-specific, AKT-kinase-driven negative feedback loop that attenuates BCR signaling. Mass spectrometry revealed that AKT target activity was altered in GCBCs compared with naive B cells. Retargeting was linked to differential AKT T308 and S473 phosphorylation, in turn controlled by GC-specific upregulation of phosphoinositide-dependent protein kinase PDK1 and the phosphatase PTEN. In GCBCs, AKT preferentially targeted CSK, SHP-1 and HPK1, which are negative regulators of BCR signaling. We found that phosphorylation enhances enzymatic activity of these proteins, creating a negative feedback loop that dampens upstream BCR signaling. AKT inhibition relieved this negative feedback and enhanced activation of BCR-proximal kinase LYN, as well as downstream BCR signaling molecules in GCBCs.
Identifiants
pubmed: 31011187
doi: 10.1038/s41590-019-0376-3
pii: 10.1038/s41590-019-0376-3
pmc: PMC6724213
mid: NIHMS1523943
doi:
Substances chimiques
Biomarkers
0
Receptors, Antigen, B-Cell
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
PTEN Phosphohydrolase
EC 3.1.3.67
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
736-746Subventions
Organisme : NIAID NIH HHS
ID : R01 AI043603
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI105018
Pays : United States
Organisme : NIH HHS
ID : S10 OD011925
Pays : United States
Commentaires et corrections
Type : CommentIn
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