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Regulation of B-cell signal transduction by adaptor proteins

Key Points

  • Adaptor molecules are crucial for B-cell function and development.

  • By using protein–protein interaction domains, such as SRC-homology 2 (SH2) and SH3 domains, adaptor molecules make intermolecular complexes, thereby contributing to the selective partitioning of binding partners into discrete subcellular locations.

  • The subcellular location of adaptors by themselves, such as exclusion or inclusion, in lipid rafts is also crucial for B-cell signal transduction.

  • Adaptor molecules can induce intramolecular conformational changes in their binding partners, thereby regulating their intrinsic enzymatic activities.

  • Because they have multiple binding partners (such as kinases and substrates), adaptor molecules can accelerate interactions between these partners.

  • Co-receptors, such as paired immunoglobulin-like receptor B (PIRB) and FcγRIIB, can be viewed also as adaptor molecules, as the tyrosine phosphorylation status of their cytoplasmic tails regulates the partitioning of protein- and lipid-phosphatases in the vicinity of the B-cell receptor signalling complex.

  • Adaptor molecules and co-receptors participate in establishing negative or positive regulatory loops, thereby fine-tuning B-cell responses.

Abstract

An important role has emerged for adaptor molecules in linking cell-surface receptors, such as the B-cell antigen receptor, with effector enzymes. Adaptor proteins direct the appropriate subcellular localization of effectors and regulate their activity by inducing conformational changes, both of which, in turn, contribute to the spatio-temporal precision of B-cell signal-transduction events. In addition, adaptor molecules participate in establishing negative- or positive-feedback regulatory loops in signalling networks, thereby fine-tuning the B-cell response.

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Figure 1: Signalling molecules that are found in B cells illustrated to highlight their modular structures and protein–protein interaction domains.
Figure 2: Raft translocation of the BCR by ligand binding.
Figure 3: Models of negative-feedback regulatory loops for LYN and BTK.
Figure 4: Phosphoinositide metabolism mediated by PI3K, SHIP, PTEN and PLCγ2.
Figure 5: Two-step models for PLCγ2 and PI3K activation.
Figure 6: Negative-regulatory loops mediated by inhibitory receptors on B cells.

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Acknowledgements

Work in my laboratory was supported by grants from the Ministry of Education, Science, Sports and Culture in Japan, the Toray Science Foundation and the Human Frontier Science Program. I thank V. Tybulewicz for communicating his preprint and the members of my laboratory for their contribution to both the work that is cited and the writing of this manuscript.

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DATABASES

Entrez

EBV

LMP2A

InterPro

ITAM

PDZ domain

PH domain

PTB domain

SH2

SH3

TH domain

LocusLink

AKT

Akt

BCAP

Bcap

BLK

BLNK

Blnk

BTK

Btk

CD19

CD21

CD22

CD45

CD79A

CD79B

CD81

CK2

CSK

DOK1

Dok1

DOK2

ERK

Erk

FcɛRI (human)

FcɛRI (mouse)

FcγRIIB

FYN

GAB1

GAB2

IBTK

inaD

LAT

LEU13

LYN

Lyn

PAG

PI3K (human)

PI3K (mouse)

PI5K

PIRB

Prkcβ

PLCγ1

PLCγ2

Plcγ2

PTEN

RAC1

SAB

Sab

SHC

SHIP

Ship

SHP1

Shp1

SLP76

SRC

Src

SYK

TEC

trp

VAV

Vav1

Vav2

Vav3

OMIM

XLA

FURTHER INFORMATION

Alliance for Cellular Signalling

RIKEN

Glossary

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF

(ITAM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several activating receptors, such as the BCR. The motif has the form Tyr-Xaa-Xaa-Leu/Ile, and the tyrosine is a target for phosphorylation by SRC tyrosine kinases and subsequent binding of proteins containing SH2 domains.

SIGNALOSOME

A putative, stable signalling complex, which consists of BTK, BLNK, BCAP, VAV1/2, PLCγ2 and PI3K, that is proposed to regulate intracellular calcium and subsequent downstream events.

PLCγ2–CALCIUM–PKCβ PATHWAY

Activated phospholipase Cγ2 (PLCγ2), presumably tyrosine phosphorylated by Bruton's tyrosine kinase (BTK), converts phosphatidylinositol-4,5-bisphosphate (PtdInsP2) into two second messengers, diacylglycerol (DAG) and InsP3. DAG activates protein kinase Cβ (PKCβ), and InsP3 causes the release of calcium from the endoplasmic reticulum through its binding to InsP3 receptors.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF

(ITIM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several inhibitory receptors, such as FcγRIIB and PIRB. The prototype six-amino-acid sequence is (Ile/Val/Leu/Ser)-Xaa-Tyr-Xaa-Xaa-Leu/Val. Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family tyrosine kinases, which provides a docking site for the recruitment of cytoplasmic phosphatases that have an SH2 domain.

B1 B CELLS

In the mouse, the B1 B-cell subset is found primarily in the peritoneal and pleural cavities. B1 B cells form a self-renewing subset with a restricted repertoire of B-cell receptors that respond to common bacterial antigens and might have a role in autoimmunity.

TI-II RESPONSE

Thymus-independent type II (TI-II) antigens, which are derived typically from polysaccharides, consist of complex repeating units that drive B-cell responses by extensive crosslinking. Both B1 and marginal-zone B cells are thought to be responsible for TI-II antibody responses.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). Proteins fused to cyan, yellow or red fluorescent proteins are expressed and assessed for interaction by measuring the energy transfer between fluors, which can only occur if proteins physically interact. This is used to measure protein–protein interactions microscopically or by a FACS-based method.

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Kurosaki, T. Regulation of B-cell signal transduction by adaptor proteins. Nat Rev Immunol 2, 354–363 (2002). https://doi.org/10.1038/nri801

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