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Review
. 2011 Jun;48(11):1319-27.
doi: 10.1016/j.molimm.2010.12.005. Epub 2011 Jan 13.

The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity

David R Gibb  1 , Sheinei J Saleem, Natalia S Chaimowitz, Joel Mathews, Daniel H Conrad
Affiliations
Review

The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity

David R Gibb et al. Mol Immunol. 2011 Jun.

Abstract

Proteolytic processing of transmembrane receptors and ligands can have a dramatic impact on cell signaling processes and subsequent cellular responses, including activation and differentiation. A member of the disintegrin and metalloproteinase family, ADAM10, has emerged as a prominent regulator of numerous receptors and ligands, including Notch and CD23. Here, we review studies resulting from the recent generation of ADAM10 conditional knockout mice which revealed a critical role for ADAM10 in Notch-dependent lymphocyte development. Additionally, we discuss results of numerous in vitro and ex vivo studies indicating that ADAM10 regulates the production of multiple secreted factors that contribute to autoimmune reactions.

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Figures

Figure 1
Figure 1. ADAM10-mediated RIP of Notch2 is required for Marginal Zone B cell development
Signaling through the Notch2 receptor expressed on transitional B cells directs marginal zone B cell differentiation(Saito et al., 2003). The Notch2 heterodimer on B cells binds ligands, Jagged 1-2 and Delta-like 1, present on stromal and antigen presenting cells. Binding initiates sequential cleavage events by ADAM10 (S2 cleavage) and a γ-secretase complex (S3 cleavage). Cleavage releases the Notch2 intracellular domain (N2ICD), containing RAM formula image, nuclear localization formula image, transactivating (TAD) formula image, EGF-repeat formula image,and PEST domains formula image. Transport of the N2ICD to the nucleus followed by binding to the transcription factor, RBP-Jĸ, allows the release of co-repressors (CoR), and attraction of co-activators (CoA) to the transcriptional complex. The activated complex transcribes Notch target genes, including CD21/35, Deltex-1, Hes 1, and Hes 5, that promote development of marginal zone B cells. Deletion of ADAM10, Notch2, and RBP-Jĸ from B cells, or Delta-like 1 from stromal cells prevents marginal zone B cell development.
Figure 2
Figure 2. ADAM10 and Notch similarly regulate B cell development
Precursors to the B cell lineage develop from common lymphoid progenitors (CLPs) in the bone marrow. Constitutive expression of the Notch intracellular domain (NICD), Hes 1 or Hes 5 in CLPs prevents B lineage commitment, while promoting T cell development. Development of the marginal zone B cell (MZB) lineage is regulated by Notch2 signaling. The majority of transitional cells differentiate into follicular B cells, which constitute the majority of circulating B cells. However, ADAM10-mediated Notch2 signaling promotes MZB lineage development. HSC-hematopoietic stem cell, CMP-common myeloid progenitor, Im-Immature. Solid arrows and dashed arrows indicate confirmed and hypothetical differentiation events, respectively.
Figure 3
Figure 3. Ectodomain shedding of CD23, a regulator of IgE-mediated inflammation
CD23 monomers, consisting of a short cytoplasmic tail, a transmembrane portion, an extracellular stalk region forming a coiled-coil structure, and a lectin head domain that binds IgE, form a homo-trimeric tertiary structure, which is stabilized by IgE binding. In the absence of IgE or the presence of anti-stalk antibodies, ADAM10 constitutively cleaves CD23 ectodomains and releases soluble CD23 (sCD23). Cleavage prevents IgE:CD23 interaction at the B cell surface, and results in elevated IgE synthesis. This figure was modified from Conrad et al.(Conrad et al., 2007).
See this image and copyright information in PMC

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