QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online July 2, 2008
doi: 10.1242/10.1242/jcs.017905

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arana, E. Articles by Batista, F. D. Search for Related Content PubMed PubMed Citation Articles by Arana, E. Articles by Batista, F. D. Social Bookmarking                         What's this?

Regulation of integrin activation through the B-cell receptor

Lymphocyte Interaction Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK

View larger version (29K): [in this window] [in a new window]   Fig. 1. Molecular mechanisms required for the activation of integrin-mediated B-cell adhesion in response to membrane-bound antigens. (A) Prior to antigen stimulation, the `resting' B cell contains BCRs and inactive integrins that are distributed throughout the membrane. Following BCR engagement with antigen on the surface of an antigen-presenting cell (APC) that expresses integrin ligands, crosslinking of BCRs initiates intracellular signalling cascades that result in the inside-out activation of integrins. The molecular details of the intracellular pathways that are shown are based on those identified by Arana et al. and Spaargaren et al. (Arana et al., 2008; Spaargaren et al., 2003). These pathways operate by mechanisms that are dependent on the reorganisation of the cytoskeleton, and allow clustering and activation of integrins as well as the subsequent formation of the immunological synapse (IS). (B) Model of a BCR expressed on the surface of a naive B cell. This BCR comprises a membrane immunoglobulin M (mIgM) in complex with the Ig-Igβ sheath. The mIgM is a heterotetrameter, consisting of two light chains (yellow) and two heavy chains (green) that form distinct Fc and Fab domains. The Fab domains are responsible for binding to antigens, whereas the Fc domain mediates effector functions of antibodies by binding to Fc receptors. The Ig-Igβ sheath allows for transmission of signalling via the BCR through phosphorylation of their immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular domains.

View larger version (48K): [in this window] [in a new window]   Fig. 2. Cellular mechanism for the inside-out activation of integrins. Following BCR stimulation with antigen on the surface of an APC, BCR-antigen microclusters form throughout the area of contact. These microclusters act as the sites for microsignalosome assembly and recruit molecules such as Syk, Vav, CD19, PLC2 (Weber et al., 2008) and PI3K (D. Depoil and F.D.B., unpublished data). We propose that these microsignalosomes provide a favourable environment for the activation of small GTPases such as Rac2 (shown in grey), which in turn mediate reorganisation of the cytoskeleton and activation of integrin-mediated B-cell adhesion. Enhanced adhesion and signalling through the BCR allow for propagation of the B-cell spreading response. We suggest that microsignalosomes are transported from the periphery to the cSMAC by centripetal retrograde actin flow in a manner similar to that recently observed in T cells (Kaizuka et al., 2007). The presence of activated integrins during spreading promotes B-cell adhesion, which stimulates the generation of further microsignalosomes and ultimately facilitates the activation of B cells.

View larger version (61K): [in this window] [in a new window]   Fig. 3. Differences in inside-out activation of integrins in B and T cells. The current understanding of the early molecular events that underlie the inside-out activation of integrins in B and T cells following immunoreceptor stimulation is shown. Differences in the composition of the signalosomes that are assembled are illustrated, in terms of their differential use of proximal signalling and adaptor molecules. Molecules that have been demonstrated to be localised within the microsignalosome by high-resolution imaging are shown (blue), as well as those that have been implicated to be important by biochemical analysis (green). The Src-family kinases (Lyn and Lck) are not strictly considered to be part of the microsignalosome because they are localised to the membrane prior to antigenic stimulation; however, they are crucial for microsignalosome formation.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

Twitter