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

First published online July 31, 2003
doi: 10.1242/10.1242/jcs.00674

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 Related articles in JCS 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 Kumanogoh, A. Articles by Kikutani, H. Search for Related Content PubMed PubMed Citation Articles by Kumanogoh, A. Articles by Kikutani, H.

Immune semaphorins: a new area of semaphorin research

Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan

View larger version (23K): [in a new window]   Fig. 1. Structure of the semaphorin family. The semaphorin family contains a large number of phylogenetically conserved secreted and transmembrane proteins. The members have been divided into eight classes based on structural features, one of which includes a unique set of viral molecules. All members of the semaphorin family share a common sema domain. Abbreviations: GPI, glycosylphosphatidylinositol-anchored; Ig, immunoglobulin-like domain; Sema, Sema domain; SS, signal sequence.

View larger version (22K): [in a new window]   Fig. 2. Sema4D uses two different receptors. Sema4D is a member of the class IV semaphorin subfamily. Several consensus sites for serine phosphorylation exist in the cytoplasmic domain. Although Sema4D is a transmembrane-type semaphorin, it can be proteolytically cleaved from the surface to produce a soluble form. Serine kinase activities associated with the cytoplasmic region of Sema4D are implicating in the regulation of Sema4D proteolytic cleavage. Sema4D uses two receptors, CD72 and plexin-B1. Sema4D exerts its effects on immune cells, such as B cells and DCs, through CD72, whereas it induces growth cone collapse and epithelial cell invasive growth through plexin-B1 and plexin-B1/Met, respectively. Of note, the extracellular region of plexin-B1 is also cleaved (Artigiani et al., 2003).

View larger version (21K): [in a new window]   Fig. 3. Sema4D exerts its biological activities responses through plexin-B1 or CD72. (a) Plexin-B1 mediates Sema4D-induced axon repulsion by coordinately regulating the activity of the Rac and Rho small GTPases. Plexin-B1 binds Rac-GTP and downregulates its activity by blocking access to PAK. Binding to the RhoGEF/PDZ-RhoGEF and LARG thereby increases the output of RhoA. During the regulation of epithelial cell invasive growth, Sema4D signals through a plexin-B1/Met receptor complex. Binding of Sema4D to plexin-B1 leads to the activation of Met. This binding event results in the phosphorylation of Met, plexin-B1 and the Met target Gab1. (b) Sema4D turns off the negative signaling of CD72. Signals from the BCR, CD40, and TLR4 are homeostatically regulated by Sema4DCD72 interactions. In the absence of Sema4D signaling, SHP-1 is associated with the ITIM of CD72. SHP-1 induces tyrosine dephosphorylation and the inactivation of several signaling effectors, including syk and lyn. Binding of Sema4D to CD72 induces the dephosphorylation of the CD72 ITIMs, resulting in the dissociation of SHP-1 from CD72.

View larger version (22K): [in a new window]   Fig. 4. Involvement of Sema4A in T cell activation through Tim-2. Sema4A, preferentially expressed on DCs and B cells, is a class IV transmembrane-type semaphorin family member. Tim-2, a member of the Tim protein family, possesses an Ig-like domain, a mucin domain, a transmembrane region, and a cytoplasmic region containing a consensus tyrosine phosphorylation site. The mucin domain has multiple putative sites for O-linked glycosylation, while the Ig domain has several sites for putative N-linked glycosylation. Following T cell activation through TCR ligation, Tim-2 expression on T cells interacts with Sema4A, resulting in enhanced T cell activation via tyrosine phosphorylation of Tim-2, acting through an unknown signaling pathway.